Novel Monocyclic And Bicyclic Ring System Substituted Carbanucleoside Analogues For Use As PRMT5 Inhibitors

ABSTRACT

The present invention relates to novel novel monocyclic and bicyclic ring system substituted carbanucleoside analogues of Formula (I), wherein the variables have the meaning defined in the claims. The compounds according to the present invention are useful as PRMT5 inhibitors. The invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

FIELD OF THE INVENTION

The present invention relates to novel monocyclic and bicyclic ringsystem substituted carbanucleoside analogues useful as PRMT5 inhibitors.The invention further relates to pharmaceutical compositions comprisingsaid compounds as an active ingredient as well as the use of saidcompounds as a medicament.

BACKGROUND OF THE INVENTION

PRMT5, also described as Hsl7, Jbpl, Skbl, Capsuleen or Dart5, is one ofthe major methyltransferases responsible for mono- and symmetricdimethylation of arginines. Post-translational arginine methylation onhistones and non-histone proteins seems to be crucial for a variety ofbiological processes, like genome organisation, transcription,differentiation, spliceosome function, signal transduction andregulation of cell-cycle progression, stem cells and T-cell fate [Stopa,N. et al, Cell Mol Life Sci, 2015. 72(11): p. 2041-59] [Geoghegan, V. etal, Nat Commun, 2015. 6: p. 6758]. Metazoan PRMT5 forms a functionalcomplex with the methylosome protein 50 (MEP50) also named as Wdr77,androgen receptor coactivator p44 and Valois. Both, elevated PRMT5-MEP50protein level and cytoplasmic accumulation are implicated in cancertumorigenesis and have recently been correlated with poor clinicaloutcome [Shilo, K. et al, Diagn Pathol, 2013. 8: p. 201]. Cellularrescue experiments that addressed both the catalytic and scaffoldfunction of the PRMT5-MEP50 complex, beside comprehensive enzymologicalstudies have substantiate the oncogenic link between protein level,localisation and enzymatic function [Gu, Z. et al, Biochem J, 2012.446(2): p. 235-41] [Di Lorenzo, A. et. al, FEBS Lett, 2011. 585(13): p.2024-31] [Chan-Penebre, E. et al, Nat Chem Biol, 2015. 11(6): p. 432-7].This correlation turns PRMT5 into an essential small molecule drugtarget against cancer and other diseases [Stopa, N. et al, Cell Mol LifeSci, 2015. 72(11): p. 2041-59].

PRMT5 is a member of the type II PRMT subfamily that utilisesS-adenosylmethionine (SAM) to generate symmetric dimethylated arginineon histones and non-histone protein substrates andS-adenosylhomocysteine (SAH). The crystal structure of the humanhetereo-octameric complex (PRMT5)₄(MEP50)₄ co-crystalised with SAH and ahistone H4 peptide substrate illustrated the mechanism of methylationand substrate recognition [Antonysamy, S. et al, Proc Natl Acad Sci USA,2012. 109(44): p. 17960-5]. The regulation of PRMT5 activity occursthrough a vast number of different binding partners, post-translationalmodification cross talk, miRNAs and subcellular localisation.

Methylation of histones H2A and H4 on Arg3 and histone H3 on Arg8regulate chromatin organisation for specific repression of genetranscripts that are involved in differentiation, transformation,cell-cycle progression and tumour suppression [Karkhanis, V. et al.,Trends Biochem Sci, 2011. 36(12): p. 633-41]. Furthermore,PRMT5-mediated methylation of histone H4 on Arg3 might recruit theDNA-methyltransferase DNMT3 A to couple histone and DNA methylation forlong-term gene silencing [Zhao, Q. et al, Nat Struct Mol Biol, 2009.16(3): p. 304-11].

Non-histone methylation can occur either in the cytoplasm or nucleusdependent on the cellular localisation of PRMT5. The methylation of theSm proteins D1 and D3, which are required for the assembly of thenuclear splicesome, takes place in the cytoplasm as part of the PRMT5containing “methylosome” [Friesen, W. J. et al, Mol Cell Biol, 2001.21(24): p. 8289-300]. Further evidence for PRMT5 involved in splicinghas been provided by the conditional PRMT5 knockout in mouse neural stemcells. Cells that lack PRMT5 showed a selective retention of introns andskipping of exons with weak 5′ donor sites [Bezzi, M. et al, Genes Dev,2013. 27(17): p. 1903-16].

In addition to a role in splicing, PRMT5 influences key pathwaysinvolved in cell fate and homeostasis by direct methylation of keysignalling nodules like p53 [Jansson, M. et al, Nat Cell Biol, 2008.10(12): p. 1431-9], EGFR [Hsu, J. M. et al, Nat Cell Biol, 2011. 13(2):p. 174-81], CRAF [Andreu-Perez, P. et al, Sci Signal, 2011. 4(190): p.ra58], PI3K/AKT [Wei, T. Y. et al, Cell Signal, 2014. 26(12): p.2940-50], NFKB [Wei, H. et al., Proc Natl Acad Sci USA, 2013. 110(33):p. 13516-21].

Since PRMT5 is one of the major sym-Arg methyltransferases and involvedin a multitude of cellular processes, an increased protein expressionappears to be an important factor in its tumourigenicity. Interestingly,the translation of PRMT5 in mantle cell lymphoma (MCL) seems to beregulated by miRNAs. Although MCL cells show less mRNA and a slowertranscription rate of PRMT5 than normal B lymphocytes, the PRMT5 leveland the methylation of H3R8 and H4R3 are significantly increased [Pal,S. et al, EMBO J, 2007. 26(15): p. 3558-69]. Re-expression of miRNAsthat binds the 3′UTR region of PRMT5 decreases PRMT5 protein level[Wang, L. et al, Mol Cell Biol, 2008. 28(20): p. 6262-77]. Strikingly, aprmt5 antisense RNA has been found within the human prmt5 gene thatsupports the hypothesis of a specific translational regulation ratherthan high mRNA expression level [Stopa, N. et al, Cell Mol Life Sci,2015. 72(11): p. 2041-59].

Although PRMT5 is considered as a clinical relevant target, very fewselective PRMT5 inhibitors have been published, yet. Very recently, anovel sub-nano molar potent PRMT5 inhibitor (EPZ0 15666) withanti-tumour activity in multiple MCL xenograft models has been describedto be the first chemical probe suitable for further validation ofPRMT5's biology and role in cancer [Chan-Penebre, E. et al., Nat ChemBiol, 2015. 11(6): p. 432-7].

Further development of specific small molecule inhibitors of PRMT5 maylead to novel chemotherapeutic approaches for cancer.

WO2016135582 and US20160244475 describe substituted nucleosidederivatives useful as anticancer agents.

WO2014100695A1 discloses compounds useful for inhibiting PRMT5 activity;Methods of using the compounds for treating PRMT5-mediated disorders arealso described.

WO2014100730A1 discloses PRMT5 inhibitors containing a dihydro- ortetrahydroisoquinoline and uses thereof.

Devkota, K. et al, ACS Med Chem Lett, 2014. 5: p. 293-297, describes thesynthesis of a series of analogues of the natural product sinefungin andthe ability of these analogues to inhibit EHMT 1 and EHMT2.

WO2003070739 discloses partial and full agonists of A1 adenosinereceptors, their preparation, and their therapeutic use.

WO2012082436 discloses compounds and compositions as modulators ofhistone methyltransferases, and for treating diseases influenced bymodulation of histone methyltransferase activity.

WO2014100719 discloses PRMT5 inhibitors and uses thereof.

WO03074083 discloses combination therapies that selectively killmethylthioadenosine phosphorylase deficient cells. Analogs of MTA aredescribed herein as anti-toxicity agents.

Kung, P.-P. et al, Bioorg Med Chem Lett, 2005. 15: p. 2829-2833,describes the design, synthesis, and biological evaluation of novelhuman 5′-deoxy-5′-methylthioadenosine phosphorylase (MTAP) substrates.

WO2012075500 discloses 7-deazapurine modulators of histonemethyltransferase.

WO2014035140 discloses compounds and compositions for modulating histonemethyltransferase activity.

WO2015200680 describes PRMT5 inhibitors and uses thereof.

WO9640686 describes heterocyclic substituted cyclopentane compounds andmethods of using such compounds for inhibiting adenosine kinase.

WO20.17032840 relates to novel 6-6 bicyclic aromatic ring substitutednucleoside analogues useful as PRMT5 inhibitors.

There is thus a strong need for novel PRMT5 inhibitors thereby openingnew avenues for the treatment or prevention of cancer, such as e.g.mantle cell lymphoma. It is accordingly an object of the presentinvention to provide such compounds.

The compounds of the present invention are structurally different andmay have improved properties such as for example improved potency, orimproved pharmacokinetics (PK) and oral bioavailability, compared withcompounds disclosed in the prior art.

SUMMARY OF THE INVENTION

It has been found that the compounds of the present invention are usefulas PRMT5 inhibitors. The compounds according to the invention andcompositions thereof, may be useful for the treatment or prevention, inparticular for the treatment, of diseases such as a blood disorder,metabolic disorders, autoimmune disorders, cancer, inflammatorydiseases, cardiovascular diseases, neurodegenerative diseases,pancreatitis, multiorgan failure, kidney diseases, platelet aggregation,sperm motility, transplantation rejection, graft rejection, lunginjuries, and the like.

The present invention concerns novel compounds of Formula (I):

whereinR¹ represents hydrogen or —C(═O)—C₁₋₄ alkyl;R² represents hydrogen or —C(═O)—C₁₋₄ alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, —CR^(5a)R^(5b)—X—,—C≡C—, —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R^(5h)—, or—CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R^(5h)—.R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R⁵ ^(h) , and R⁵^(i) each independently represent hydrogen or Ci-4alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH-Ci-4alkyl, and —N(Ci-₄alkyl)₂;Ar represents a monocyclic aromatic ring or a bicyclic ring system;wherein the monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;wherein the bicyclic ring system is

-   -   (i) a 9-membered bicyclic aromatic ring system consisting of a        6-membered ring fused with a 5-membered ring, containing one,        two or three heteroatoms each independently selected from O, S,        and N,        -   said 9-membered bicyclic aromatic ring being attached to the            remainder of the molecule via a ring carbon atom of the 5-            or 6-membered ring, or a ring nitrogen atom of the            5-membered ring; or    -   (ii) a 10-membered bicyclic aromatic ring system consisting of        two fused 6-membered rings, wherein optionally 1 or 2 ring        carbon atoms are replaced by a nitrogen atom; provided that when        the nitrogen atom replaces one of the two fused carbon atoms, a        carbonyl group is present in said bicyclic aromatic ring system;        -   provided that in case Ar represents a 10-membered bicyclic            aromatic ring system, Z can only represent            —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) — or —CR^(5a)R⁵            ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —; or    -   (iii) a fused bicyclic partially aromatic ring system which is        attached with the aromatic ring to linker Z, wherein the fused        bicyclic partially aromatic ring system is selected from (b-1),        (b-2) and (b-3)

-   -   -   wherein ring A is a monocyclic aromatic ring is selected            from the group consisting of pyridinyl, pyrimidinyl,            pyrazolyl and imidazolyl;        -   wherein ring B is a C₅-ecycloalkyl or a 5- to 6-membered            saturated heterocyclyl containing one or two heteroatoms            each independently selected from O, S and N;            Ar is optionally substituted on the carbon atoms with in            total one, two, three or four substituents each            independently selected from the group consisting of halo,            oxo, —OH, —NH₂, —NH—Ci_₄alkyl, —NHR¹⁰cyano, —CF₃,            Ci_₄alkyloxy, C₃₋₆cycloalkyl,

    -   0-C₃_6 cycloalkyl, C₂-₆alkenyl, Ci_₄alkyl, and        Ci_₄alkyl substituted with one Ci_₄alkyloxy; and        where possible Ar is optionally substituted on one N-atom with        one substituent selected from the group consisting of Ci_₄alkyl;        C₃-₆cycloalkyl; Ci_₄alkyl substituted with one, two or three        halo atoms; and C₃₋₆cycloalkyl substituted with one, two or        three halo atoms;        R¹⁰ represents —(C=0)-Ci-4alkyl; C₃-₆cycloalkyl; R¹³; R¹⁴;        C3-₆cycloalkyl substituted with one, two or three substituents        each independently selected from the group consisting of halo,        —OH and -0-Ci-4alkyl; Ci-4alkyl substituted with one, two or        three substituents each independently selected from the group        consisting of halo, —OH and -0-Ci_4 alkyl; or Ci-4alkyl        substituted with one substituent selected from the group        consisting of C3-6cycloalkyl, R¹³ and R¹⁴;        R¹³ represents a 4- to 7-membered monocyclic aromatic ring        containing one, two or three heteroatoms each independently        selected from O, S, S(=0)_(p) and N; said 4- to 7-membered        monocyclic aromatic ring is optionally substituted with one or        two substituents selected from the group consisting of        Ci-4alkyl;        p represents 1 or 2;        R¹⁴ represents phenyl optionally substituted with one, two or        three substituents each independently selected from the group        consisting of halo;        Het represents a bicyclic aromatic heterocyclic ring system        selected from the group consisting of (a-1), (a-2) and (a-3):

R³ ^(a) , R³ ^(d) and R^(3e) each independently represent hydrogen,halo, —NR⁷ ^(a) R^(7b), Ci_4 alkyl, C₂_4 alkenyl, C3-₆cycloalkyl, —OH,or -0-Ci-4alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, C3-₆cycloalkyl, or Ci-4alkyl;R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently representhydrogen, halo, —NR⁸ ^(a) R^(8b), or C₁₋₄alkyl;R⁸ ^(a) and R^(8b) each independently represent hydrogen or Ci-4alkyl;Q¹ represents N or CR⁶ ^(a) ;Q² represents N or CR^(6b);Q⁸ represents N or CR^(6g);Q⁹ represents N or CR^(6h);Q¹⁰ represents N or CR^(6i);Q¹¹ represents N or CR^(6j);Q⁵ represents CR^(3d); Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents CR^(3d); Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents N;R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each independentlyrepresent hydrogen, halogen, Ci_₄alkyl, —NR⁹ ^(a) R^(9b), or Ci-4alkylsubstituted with one, two or three halo atoms;R⁹ ^(a) and R^(9b) each independently represent hydrogen or Ci-4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.

The present invention also concerns methods for the preparation ofcompounds of the present invention and pharmaceutical compositionscomprising them.

The compounds of the present invention were found to inhibit PRMT5 perse or can undergo metabolism to a (more) active form in vivo (prodrugs),and therefore may be useful in the treatment or prevention, inparticular in the treatment, of diseases such as a blood disorder,metabolic disorders, autoimmune disorders, cancer, inflammatorydiseases, cardiovascular diseases, neurodegenerative diseases,pancreatitis, multiorgan failure, kidney diseases, platelet aggregation,sperm motility, transplantation rejection, graft rejection, lunginjuries, and the like.

In view of the aforementioned pharmacology of the compounds of Formula(I) and pharmaceutically acceptable addition salts, and solvatesthereof, it follows that they may be suitable for use as a medicament.

In particular the compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, may be suitable in thetreatment or prevention, in particular in the treatment, of any one ofthe diseases or conditions mentioned hereinbefore or hereinafter, inparticular cancer.

The present invention also concerns the use of compounds of Formula (I)and pharmaceutically acceptable addition salts, and solvates thereof,for the manufacture of a medicament for the inhibition of PRMT5, for thetreatment or prevention of any one of the diseases or conditionsmentioned hereinbefore or hereinafter, in particular cancer.

The present invention will now be further described. In the followingpassages, different aspects of the invention are defined in more detail.Each aspect so defined may be combined with any other aspect or aspectsunless clearly indicated to the contrary. In particular, any featureindicated as being preferred or advantageous may be combined with anyother feature or features indicated as being preferred or advantageous.

DETAILED DESCRIPTION

When describing the compounds of the invention, the terms used are to beconstrued in accordance with the following definitions, unless a contextdictates otherwise.

When any variable occurs more than one time in any constituent or in anyformula (e.g. Formula (I)), its definition in each occurrence isindependent of its definition at every other occurrence.

Whenever the term “substituted” is used in the present invention, it ismeant, unless otherwise is indicated or is clear from the context, toindicate that one or more hydrogens, in particular from 1 to 3hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, onthe atom or radical indicated in the expression using “substituted” arereplaced with a selection from the indicated group, provided that thenormal valency is not exceeded, and that the substitution results in achemically stable compound, i.e. a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and formulation into a therapeutic agent.

When two or more substituents are present on a moiety they may, unlessotherwise is indicated or is clear from the context, replace hydrogenson the same atom or they may replace hydrogen atoms on different atomsin the moiety.

The prefix “C_(x)-_(y)” (where x and y are integers) as used hereinrefers to the number of carbon atoms in a given group. Thus, a Ci-4alkylgroup contains from 1 to 4 carbon atoms, a Ci_3 alkyl group containsfrom 1 to 3 carbon atoms and so on.

The term “halo” as a group or part of a group is generic for fluoro,chloro, bromo, iodo unless otherwise is indicated or is clear from thecontext.

The term “Ci-4alkyl” as a group or part of a group refers to ahydrocarbyl radical of Formula C_(n)H_(2n)+i wherein n is a numberranging from 1 to 4. Ci-4alkyl groups comprise from 1 to 4 carbon atoms,preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbonatoms. Ci-4alkyl groups may be linear or branched and may be substitutedas indicated herein. When a subscript is used herein following a carbonatom, the subscript refers to the number of carbon atoms that the namedgroup may contain. Ci-4alkyl includes all linear, or branched alkylgroups with between 1 and 4 carbon atoms, and thus includes methyl,ethyl, n-propyl, l-propyl, 2-methyl-ethyl, butyl and its isomers (e.g.n-butyl, /sobutyl and /er/-butyl), and the like.

The skilled person will realize that the term ‘Ci-4alkoxy’ or‘Ci-4alkyloxy’ as a group or part of a group refers to a radical havingthe Formula —OR^(c) wherein RC is Ci-4alkyl. Non-limiting examples ofsuitable Ci-4alkyloxy include methyloxy (also methoxy), ethyloxy (alsoethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxyand tert-butyloxy.

The term “C2-4alkenyl” as used herein as a group or part of a grouprepresents a straight or branched chain hydrocarbon group containingfrom 2 to 4 carbon atoms and containing a carbon carbon double bond suchas, but not limited to, ethenyl, propenyl, butenyl, 1-propen-2-yl, andthe like.

The term “C2-6alkenyl” as used herein as a group or part of a grouprepresents a straight or branched chain hydrocarbon group containingfrom 2 to 6 carbon atoms and containing a carbon carbon double bond suchas, but not limited to, ethenyl, propenyl, butenyl, pentenyl,1-propen-2-yl, hexenyl and the like.

The term ‘C3-6cycloalkyl’ as used herein as a group or part of a grouprepresents cyclic saturated hydrocarbon radicals having from 3 to 6carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The term ‘C5-6cycloalkyl’ as used herein as a group or part of a grouprepresents cyclic saturated hydrocarbon radicals having from 5 to 6carbon atoms such as cyclopentyl or cyclohexyl.

The term “oxo” means the double-bonded group (=0) attached as asubstituent.

In case Z is —X—CR^(5a)R^(5b)—, it is intended that X is attached to Ar.

In case Z is —CR^(5c)═CR^(5d)—, it is intended that the C-atom with theR^(5c) substituent is attached to Ar.

In case Z is —CR^(5e)R^(5g)—CR^(5i)R^(5h)—, it is intended that theC-atom with the R^(5e) and R^(5g) substituents is attached to Ar.

In case Z is —CR^(5a)R^(5b)—X—, it is intended that the C-atom with theR^(5a) and R^(5b) substituents is attached to Ar.

It will be clear for the skilled person that, unless otherwise isindicated or is clear from the context, a substituent on a 4- to7-membered monocyclic aromatic ring containing one, two or threeheteroatoms (as in the definition of R¹³) (non-limiting examples arepyrrolyl, pyridinyl, furanyl, and the like), may replace any hydrogenatom on a ring carbon atom or where possible on a ring nitrogen atom (inwhich case a hydrogen on a nitrogen atom may be replaced by asubstituent).

A 4- to 7-membered monocyclic aromatic ring containing one, two or threeheteroatoms (as in the definition of R¹ ³ ), may be attached to theremainder of the molecule of Formula (I) through any available ringcarbon or nitrogen atom as appropriate, if not otherwise specified.

The skilled person will realize that typical 4- to 7-membered monocyclicaromatic rings will be 5- or 6-membered monocyclic aromatic rings suchas for example pyrrolyl, pyridinyl, furanyl, and the like.

In case Ar represents imidazolyl it may be attached to the remainder ofthe molecule via a ring carbon or ring nitrogen atom.

Non-limiting, examples of the Ar group being a 9-membered bicyclicaromatic ring system consisting of a 6-membered ring fused with a5-membered ring, containing one, two or three heteroatoms eachindependently selected from O, S, and N, are

said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;each of which are optionally substituted according to any of theembodiments.

In case Ar represents a 10-membered bicyclic aromatic ring systemconsisting of two fused 6-membered rings, wherein a nitrogen atomreplaces one of the two fused carbon atoms in the Ar group, a carbonylgroup is present in said bicyclic aromatic ring system as exemplified bythe structure shown below:

which is optionally substituted according to any of the embodiments. Itwill be clear this example is non-limiting.

Other, non-limiting, examples of the Ar group being a 10-memberedbicyclic aromatic ring system consisting of two fused 6-membered rings,wherein optionally 1 or 2 ring carbon atoms are replaced by a nitrogenatom, are shown below:

each of which are optionally substituted according to any of theembodiments.

Non-limiting examples of the Ar group being a fused bicyclic partiallyaromatic ring system which is attached with the aromatic ring to linkerZ, are shown below:

each of which are optionally substituted according to any of theembodiments.

Whenever substituents are represented by chemical structure, “-”represents the bond of attachment to the remainder of the molecule ofFormula (I).

It will be clear that lines drawn from substituents into ring systemsindicate that the bond may be attached to any of the suitable ringatoms, unless otherwise is indicated or is clear from the context.

The term “subject” as used herein, refers to an animal, preferably amammal (e.g. cat, dog, primate or human), more preferably a human, whois or has been the object of treatment, observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medicinal doctor orother clinician, which includes alleviation or reversal of the symptomsof the disease or disorder being treated.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “treatment”, as used herein, is intended to refer to allprocesses wherein there may be a slowing, interrupting, arresting orstopping of the progression of a disease, but does not necessarilyindicate a total elimination of all symptoms.

The term “compounds of the (present) invention” as used herein, is meantto include the compounds of Formula (I) and pharmaceutically acceptableaddition salts, and solvates thereof.

Some of the compounds of Formula (I) may also exist in their tautomericform. The term “tautomer” or “tautomeric form” refers to structuralisomers of different energies which are interconvertible via a lowenergy barrier. For example, proton tautomers (also known as prototropictautomers) include interconversions via migration of a proton, such asketo-enol and imine-enamine isomerisations. Valence tautomers includeinterconversions by reorganisation of some of the bonding electrons.Such forms in so far as they may exist, although not explicitlyindicated in the above Formula (I), are intended to be included withinthe scope of the present invention.

As used herein, any chemical formula with bonds shown only as solidlines and not as solid wedged or hashed wedged bonds, or otherwiseindicated as having a particular configuration (e.g. R, S) around one ormore atoms, contemplates each possible stereoisomer, or mixture of twoor more stereoisomers. Where the stereochemistry of any particularchiral atom is not specified in the structures shown herein, then allstereoisomers are contemplated and included as the compounds of theinvention, either as a pure stereoisomer or as a mixture of two or morestereoisomers.

Hereinbefore and hereinafter, the term “compound of Formula (I)” ismeant to include the stereoisomers thereof and the tautomeric formsthereof. However where stereochemistry, as mentioned in the previousparagraph, is specified by bonds which are shown as solid wedged orhashed wedged bonds, or are otherwise indicated as having a particularconfiguration (e.g. R, 5), then that stereoisomer is so specified anddefined. It will be clear this also applies to subgroups of Formula (I).

It follows that a single compound may, where possible, exist in bothstereoisomeric and tautomeric form.

The terms “stereoisomers”, ‘“stereoisomeric forms” or “stereochemicallyisomeric forms” hereinbefore or hereinafter are used interchangeably.

Enantiomers are stereoisomers that are non-superimposable mirror imagesof each other. A 1:1 mixture of a pair of enantiomers is a racemate orracemic mixture.

Atropisomers (or atropoisomers) are stereoisomers which have aparticular spatial configuration, resulting from a restricted rotationabout a single bond, due to large steric hindrance. All atropisomericforms of the compounds of Formula (I) are intended to be included withinthe scope of the present invention.

Diastereomers (or diastereoisomers) are stereoisomers that are notenantiomers, i.e. they are not related as mirror images. If a compoundcontains a double bond, the substituents may be in the E or the Zconfiguration. Substituents on bivalent cyclic (partially) saturatedradicals may have either the cis- or trans-configuration; for example ifa compound contains a disubstituted cycloalkyl group, the substituentsmay be in the cis or trans configuration. Therefore, the inventionincludes enantiomers, atropisomers, diastereomers, racemates, E isomers,Z isomers, cis isomers, trans isomers and mixtures thereof, wheneverchemically possible.

The meaning of all those terms, i.e. enantiomers, atropisomers,diastereomers, racemates, E isomers. Z isomers, cis isomers, transisomers and mixtures thereof are known to the skilled person.

The absolute configuration is specified according to theCahn-lngold-Prelog system. The configuration at an asymmetric atom isspecified by either R or S. Resolved stereoisomers whose absoluteconfiguration is not known can be designated by (+) or (−) depending onthe direction in which they rotate plane polarized light. For instance,resolved enantiomers whose absolute configuration is not known can bedesignated by (+) or (−) depending on the direction in which they rotateplane polarized light.

When a specific stereoisomer is identified, this means that saidstereoisomer is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, in particular less than 2% and most preferablyless than 1%, of the other stereoisomers. Thus, when a compound ofFormula (I) is for instance specified as (R), this means that thecompound is substantially free of the (S) isomer; when a compound ofFormula (I) is for instance specified as E, this means that the compoundis substantially free of the Z isomer; when a compound of Formula (I) isfor instance specified as cis, this means that the compound issubstantially free of the trans isomer.

For therapeutic use, salts of the compounds of Formula (I) and solvatesthereof, are those wherein the counterion is pharmaceuticallyacceptable. However, salts of acids and bases which arenon-pharmaceutically acceptable may also find use, for example, in thepreparation or purification of a pharmaceutically acceptable compound.All salts, whether pharmaceutically acceptable or not are includedwithin the ambit of the present invention.

Pharmaceutically-acceptable salts include acid addition salts and baseaddition salts. Such salts may be formed by conventional means, forexample by reaction of a free acid or a free base form with one or moreequivalents of an appropriate acid or base, optionally in a solvent, orin a medium in which the salt is insoluble, followed by removal of saidsolvent, or said medium, using standard techniques (e.g. in vacuo, byfreeze-drying or by filtration). Salts may also be prepared byexchanging a counter-ion of a compound of the invention in the form of asalt with another counter-ion, for example using a suitable ion exchangeresin.

The pharmaceutically acceptable addition salts as mentioned hereinaboveor hereinafter are meant to comprise the therapeutically activenon-toxic acid and base addition salt forms which the compounds ofFormula (I) and solvates thereof, are able to form.

Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), maIonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids. Conversely said salt formscan be converted by treatment with an appropriate base into the freebase form.

The compounds of Formula (I) and solvates thereof containing an acidicproton may also be converted into their non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases.

Appropriate base salt forms comprise, for example, the ammonium salts,the alkali and earth alkaline metal salts, e.g. the lithium, sodium,potassium, magnesium, calcium salts and the like, salts with organicbases, e.g. primary, secondary and tertiary aliphatic and aromaticamines such as methylamine, ethylamine, propylamine, isopropylamine, thefour butylamine isomers, dimethylamine, diethylamine, diethanolamine.

dipropylaminc, diisopropylaminc, di-n-butylaminc, pyrrolidine,piperidine, morpholinc, trimethylamine, triethylamine, tripropylamine,quinuclidinc, pyridine, quinoline and isoquinoline; the benzathine,N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids suchas, for example, arginine, lysine and the like. Conversely the salt formcan be converted by treatment with acid into the free acid form.

For the purposes of this invention prodrugs are also included within thescope of the invention.

The term “prodrug” of a relevant compound of the invention includes anycompound that, following oral or parenteral administration, inparticular oral administration, is metabolised in vivo to a form thatcompound in an experimentally-detectable amount, and within apredetermined time (e.g. within a dosing interval of between 6 and 24hours (i.e. once to four times daily)). For the avoidance of doubt, theterm “parenteral” administration includes all forms of administrationother than oral administration, in particular intravenous (IV),intramuscular (IM), and subcutaneous (SC) injection. Prodrugs may beprepared by modifying functional groups present on the compound in sucha way that the modifications are cleaved, in vivo when such prodrug isadministered to a mammalian subject. The modifications typically areachieved by synthesising the parent compound with a prodrug substituent.In general, prodrugs include compounds of the invention wherein ahydroxyl, amino, sulfliydryl, carboxy or carbonyl group in a compound ofthe invention is bonded to any group that may be cleaved in vivo toregenerate the free hydroxyl, amino, sulfliydryl, carboxy or carbonylgroup, respectively; in particular wherein a hydroxyl group in acompound of the invention is bonded to any group (e.g. —C(═O)—C₁₋₄alkyl)that may be cleaved in vivo to regenerate the free hydroxyl. Within thecontext of this invention, prodrugs in particular are compounds ofFormula (I) or subgroups thereof wherein R¹ and/or R² represent—C(═O)—C₁₋₄ alkyl.

Examples of prodrugs include, but are not limited to, esters andcarbamates of hydroxy functional groups, esters groups of carboxylfunctional groups, N-acyl derivatives and N-Mannich bases. Generalinformation on prodrugs may be found e.g. in Bundegaard, H. “Design ofProdrugs” p. 1-92, Elesevier, New York-Oxford (1985).

The term solvate comprises the hydrates and solvent addition forms whichthe compounds of Formula (I) are able to form, as well aspharmaceutically acceptable addition salts thereof. Examples of suchforms are e.g. hydrates, alcoholates and the like.

The compounds of the invention as prepared in the processes describedbelow may be synthesized in the form of mixtures of enantiomers, inparticular racemic mixtures of enantiomers, that can be separated fromone another following art-known resolution procedures. A manner ofseparating the enantiomeric forms of the compounds of Formula (I), andpharmaceutically acceptable addition salts, and solvates thereof,involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemical{circumflex over ( )} isomeric forms ofthe appropriate starting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound would be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature (or the most abundant one found in nature).

All isotopes and isotopic mixtures of any particular atom or element asspecified herein are contemplated within the scope of the compounds ofthe invention, either naturally occurring or synthetically produced,either with natural abundance or in an isotopically enriched form.Exemplary isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ¾, “C,¹³C, ¹⁴C, ¹ ³ N, ¹ ⁵ 0, ¹⁷o, ¹⁸0, ³²P, ³³P, ³ ⁵ S, ¹⁸F, ³⁶Ci, ¹²²I,¹²³I, ¹ ² ⁵1, ¹ ³ ¹1, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, theradioactive isotope is selected from the group of ²H, ³H, “C and ¹⁸F.More preferably, the radioactive isotope is ²H. In particular,deuterated compounds are intended to be included within the scope of thepresent invention.

Certain isotopically-labeled compounds of the present invention (e.g.,those labeled with ³H and ¹ ⁴ C) are useful for substrate tissuedistribution assays. Tritiated (1-f) and carbon-₁₄ (¹ ⁴ C) isotopes areuseful for their ease of preparation and detectability. Further,substitution with heavier isotopes such as deuterium (i.e., ²H mayafford certain therapeutic advantages resulting from greater metabolicstability (e.g., increased in vivo half-life or reduced dosagerequirements) and hence may be preferred in some circumstances. Positronemitting isotopes such as ¹⁵0, ¹ ³ N, ¹¹C and ¹⁸F are useful forpositron emission tomography (PET) studies to examine substrate receptoroccupancy.

In an embodiment, the present invention concerns novel compounds ofFormula (I),

whereinR¹ represents hydrogen or —C(=0)-Ci-4alkyl;R² represents hydrogen or —C(═O)—C₁₋₄alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R^(5h)—,—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —, or—CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —;R^(5a), R⁵ ^(b) R^(5c), R^(5d), R^(5e), R^(5f), R⁵ ^(g) , R⁵ ^(h) , andR⁵ ^(i) each independently represent hydrogen or Ci-4alkyl;X represents -0-;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH-Ci-4alkyl, and —N(Ci-₄alkyl)₂;Ar represents a monocyclic aromatic ring or a bicyclic ring system;wherein the monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;wherein the bicyclic ring system is

-   -   (i) a 9-membered bicyclic aromatic ring system consisting of a        6-membered ring fused with a 5-membered ring, containing one,        two or three heteroatoms each independently selected from O, S,        and N, said 9-membered bicyclic aromatic ring being attached to        the remainder of the molecule via a ring carbon atom of the 5-        or 6-membered ring, or a ring nitrogen atom of the 5-membered        ring; or    -   (ii) a 10-membered bicyclic aromatic ring system consisting of        two fused 6-membered rings, wherein optionally 1 or 2 ring        carbon atoms are replaced by a nitrogen atom; provided that when        the nitrogen atom replaces one of the two fused carbon atoms, a        carbonyl group is present in said bicyclic aromatic ring system;        -   provided that in case Ar represents a 10-membered bicyclic            aromatic ring system, Z can only represent            —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) — or CR^(5a)R⁵            ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —; or    -   (iii) a fused bicyclic partially aromatic ring system which is        attached with the aromatic ring to linker Z, wherein the fused        bicyclic partially aromatic ring system is selected from (b-1),        (b-2) and (b-3)

-   -   -   wherein ring A is a monocyclic aromatic ring is selected            from the group consisting of pyridinyl, pyrimidinyl,            pyrazolyl and imidazolyl;        -   wherein ring B is a C₅-ecycloalkyl or a 5- to 6-membered            saturated heterocyclyl containing one or two heteroatoms            each independently selected from O, S and N;            Ar is optionally substituted on the carbon atoms with in            total one, two, three or four substituents each            independently selected from the group consisting of halo,            oxo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃,            Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃_6cycloalkyl,            C₂-₆alkenyl, Ci_₄alkyl, and            Ci_₄alkyl substituted with one Ci_₄alkyloxy; and            where possible Ar is optionally substituted on one N-atom            with one substituent selected from the group consisting of            Ci_₄alkyl; C₃-₆cycloalkyl; Ci_₄alkyl substituted with one,            two or three halo atoms; and C₃-₆cycloalkyl substituted with            one, two or three halo atoms;            R¹⁰ represents —(C=0)-Ci_₄alkyl; C₃-₆cycloalkyl; R¹³; R¹⁴;            C₃-₆cycloalkyl substituted with one, two or three            substituents each independently selected from the group            consisting of halo, —OH and -0-Ci_₄alkyl; Ci_₄alkyl            substituted with one, two or three substituents each            independently selected from the group consisting of halo,            —OH and -0-Ci_₄alkyl; or Ci_₄alkyl substituted with one            substituent selected from the group consisting of            C₃_6cycloalkyl, R¹³ and R¹⁴;            R¹³ represents a 4- to 7-membered monocyclic aromatic ring            containing one, two or three heteroatoms each independently            selected from O, S, S(=0)_(p) and N; said 4- to 7-membered            monocyclic aromatic ring is optionally substituted with one            or two substituents selected from the group consisting of            Ci_₄alkyl;            p represents 1 or 2;            R¹⁴ represents phenyl optionally substituted with one, two            or three substituents each independently selected from the            group consisting of halo;            Het represents a bicyclic aromatic heterocyclic ring system            (a-1);            R^(3a) represents halo, —NR⁷ ^(a) R^(7b), or -0-Ci_₄alkyl;            R^(7a) represents hydrogen;            R^(7b) represents hydrogen, C₃-₆cycloalkyl, or Ci_₄alkyl;            R^(4a) represents hydrogen, halo, —NR⁸ ^(a) R^(8b), or            Ci_₄alkyl;            R⁸ ^(a) and R^(8b) each independently represent hydrogen or            Ci_₄alkyl;            Q¹ represents CR⁶ ^(a) ;            Q² represents CR^(6b);            R⁶ ^(a) and R^(6b) each independently represent hydrogen,            halogen, Ci_₄alkyl, —NR ^(9a)R^(9b), or Ci_₄alkyl            substituted with one, two or three halo atoms;

R^(9a) and R^(9b) each independently represent hydrogen or Ci-₄alkyl;

and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I).

whereinR¹ represents hydrogen or —C(═O)—C₁₋₄alkyl;R² represents hydrogen or —C(═O)—C₁₋₄alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —,—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, or —CR^(5a)R⁵ ^(b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —;R^(5a), R⁵ ^(b) R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), and R⁵^(i) each independently represent hydrogen or Ci-4alkyl;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH-Ci-4alkyl, and —N(Ci-₄alkyl)₂;Ar represents a monocyclic aromatic ring or a bicyclic ring system;wherein the monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;wherein the bicyclic ring system is

-   -   (i) a 9-membered bicyclic aromatic ring system consisting of a        6-membered ring fused with a 5-membered ring, containing one,        two or three heteroatoms each independently selected from O, S,        and N, said 9-membered bicyclic aromatic ring being attached to        the remainder of the molecule via a ring carbon atom of the 5-        or 6-membered ring, or a ring nitrogen atom of the 5-membered        ring; or    -   (ii) a 10-membered bicyclic aromatic ring system consisting of        two fused 6-membered rings, wherein optionally 1 or 2 ring        carbon atoms are replaced by a nitrogen atom; provided that when        the nitrogen atom replaces one of the two fused carbon atoms, a        carbonyl group is present in said bicyclic aromatic ring system;        -   provided that in case Ar represents a 10-membered bicyclic            aromatic ring system, Z can only represent            —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) — or _CR^(5a)R⁵            ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R^(5h)—; or    -   (iii) a fused bicyclic partially aromatic ring system which is        attached with the aromatic ring to linker Z, wherein the fused        bicyclic partially aromatic ring system is selected from (b-1),        (b-2) and (b-3)

-   -   -   wherein ring A is a monocyclic aromatic ring is selected            from the group consisting of pyridinyl, pyrimidinyl,            pyrazolyl and imidazolyl;        -   wherein ring B is a C₅₋ecycloalkyl or a 5- to 6-membered            saturated heterocyclyl containing one or two heteroatoms            each independently selected from O, S and N;            Ar is optionally substituted on the carbon atoms with in            total one, two, three or four substituents each            independently selected from the group consisting of halo,            oxo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃,            Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃_6 cycloalkyl,            C₂-₆alkenyl, Ci_₄alkyl, and            Ci_₄alkyl substituted with one Ci_₄alkyloxy; and            where possible Ar is optionally substituted on one N-atom            with one substituent selected from the group consisting of            Ci_₄alkyl; C₃-₆cycloalkyl; Ci_₄alkyl substituted with one,            two or three halo atoms; and C₃-₆cycloalkyl substituted with            one, two or three halo atoms;            R¹⁰ represents —(C=0)-Ci_₄alkyl; C₃-₆cycloalkyl; R¹³; R¹⁴;            C₃-₆cycloalkyl substituted with one, two or three            substituents each independently selected from the group            consisting of halo, —OH and -0-Ci_₄alkyl; Ci_₄alkyl            substituted with one, two or three substituents each            independently selected from the group consisting of halo,            —OH and -0-Ci_₄alkyl; or Ci_₄alkyl substituted with one            substituent selected from the group consisting of C₃_6            cycloalkyl, R¹³ and R¹⁴;            R¹³ represents a 4- to 7-membered monocyclic aromatic ring            containing one, two or three heteroatoms each independently            selected from O, S, S(=0)_(p) and N; said 4- to 7-membered            monocyclic aromatic ring is optionally substituted with one            or two substituents selected from the group consisting of            Ci_₄alkyl;            p represents 1 or 2;            R¹⁴ represents phenyl optionally substituted with one, two            or three substituents each independently selected from the            group consisting of halo;            Het represents a bicyclic aromatic heterocyclic ring system            (a-1);            R³ ^(a) represents halo, —NR⁷ ^(a) R^(7b), or -0-Ci_₄alkyl;            R⁷ ^(a) represents hydrogen;            Rib represents hydrogen, C₃-₆cycloalkyl, or Ci_₄alkyl;            R^(4a) represents hydrogen, halo, —NR⁸ ^(a) R^(8b), or            Ci_₄alkyl;            R⁸ ^(a) and R^(8b) each independently represent hydrogen or            Ci-4alkyl;            Q¹ represents CR⁶ ^(a) ;            Q² represents CR^(6b);            R⁶ ^(a) and R^(6b) each independently represent hydrogen,            halogen, Ci-4alkyl, —NR⁹ ^(a) R^(9b), or Ci_4alkyl            substituted with one, two or three halo atoms;            R⁹ ^(a) and R^(9b) each independently represent hydrogen or            Ci-4alkyl;            and pharmaceutically acceptable addition salts, and solvates            thereof.            In an embodiment, the present invention concerns novel            compounds of Formula (I).            wherein            R¹ represents hydrogen or —C(=0)-Ci-4alkyl;            R² represents hydrogen or —C(=0)-Ci-4alkyl;            Y represents —CH₂— or —CF₂—;            Z represents —CH₂—, —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—,            —CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —, —CR^(5a)R⁵ ^(b) —X—, or            —C≡C—;            R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), and            R^(5h) each independently represent hydrogen or Ci_₄alkyl;            X represents -0-, —S—, or —NR¹¹—;            R¹¹ represents hydrogen, C₁₋₄alkyl, or C₁₋₄alkyl substituted            with one substituent selected from the group consisting of            —OH, -0-C₁₋₄alkyl, —NH₂, —NH—C₁₋₄alkyl, and —N(Ci-₄alkyl)₂;            Ar represents a monocyclic aromatic ring selected from            pyridinyl and imidazolyl; or a 9-membered bicyclic aromatic            ring system consisting of a 6-membered ring fused with a            5-membered ring, containing one, two or three heteroatoms            each independently selected from O, S, and N,            said 9-membered bicyclic aromatic ring being attached to the            remainder of the molecule via a ring carbon atom of the 5-            or 6-membered ring, or a ring nitrogen atom of the            5-membered ring;            Ar is optionally substituted on the carbon atoms with in            total one, two, three or four substituents each            independently selected from the group consisting of halo,            —OH, —NH₂, —NH—C₁₋₄alkyl, —NHR¹⁰, cyano, —CF₃, Ci-4alkyloxy,            C₃-ecycloalkyl, -0-C₃-ecycloalkyl, C₂-₆alkenyl, Ci-4alkyl,            and Ci-4alkyl substituted with one Ci-4alkyloxy; and            where possible Ar is optionally substituted on one N-atom            with one substituent selected from the group consisting of            Ci-4alkyl; C₃-₆cycloalkyl; Ci-4alkyl substituted with one,            two or three halo atoms; and C₃-₆cycloalkyl substituted with            one, two or three halo atoms;            R¹⁰ represents —(C═O)—C₁₋₄alkyl; C3-6cycloalkyl; R¹³; R¹⁴;            C3_₆cycloalkyl substituted with one, two or three            substituents each independently selected from the group            consisting of halo, —OH and —O-Ci-4alkyl; Ci-4alkyl            substituted with one, two or three substituents each            independently selected from the group consisting of halo,            —OH and -0-Ci_4 alkyl; or Ci-4alkyl substituted with one            substituent selected from the group consisting of            C3-6cycloalkyl, R¹³ and R¹⁴;            R¹³ represents a 4- to 7-membered monocyclic aromatic ring            containing one, two or three heteroatoms each independently            selected from O, S, S(=0)_(p) and N; said 4- to 7-membered            monocyclic aromatic ring is optionally substituted with one            or two substituents selected from the group consisting of            Ci-4alkyl;            p represents 1 or 2;            R¹⁴ represents phenyl optionally substituted with one, two            or three substituents each independently selected from the            group consisting of halo;            Het represents a bicyclic aromatic heterocyclic ring system            selected from the group consisting of (a-1), (a-2) and            (a-3);            R³ ^(a) , R³ ^(d) and R^(3e) each independently represent            hydrogen, halo, —NR⁷ ^(a) R^(7b),            Ci_4 alkyl, C₂_4 alkenyl, C3_₆cycloalkyl, —OH, or            -0-Ci-4alkyl;            R⁷ ^(a) represents hydrogen;            R^(7b) represents hydrogen, C3_₆cycloalkyl, or Ci-4alkyl;            R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently            represent hydrogen, halo, —NR⁸ ^(a) R^(8b), or Ci_₄alkyl;            R⁸ ^(a) and R^(8b) each independently represent hydrogen or            Ci-4alkyl;            Q¹ represents N or CR⁶ ^(a) ;            Q² represents N or CR^(6b);            Q⁸ represents N or CR^(6g);            Q⁹ represents N or CR^(6h);            Q¹⁰ represents N or CR^(6i);            Q¹¹ represents N or CR^(6j);            Q⁵ represents CR³ ^(d) ; Q⁶ represents N; and Q⁷ represents            CR^(4f); or            Q⁵ represents CR³ ^(d) ; Q⁶ represents CR^(4e); and Q⁷            represents N; or            Q⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents            CR^(4f); or            Q⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N;            or            Q⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f);            or            Q⁵ represents N; Q⁶ represents N; and Q⁷ represents N;            R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each            independently represent hydrogen, halogen, Ci_₄alkyl, —NR ⁹            ^(a) R^(9b), or Ci-4alkyl substituted with one, two or three            halo atoms;            R⁹ ^(a) and R^(9b) each independently represent hydrogen or            Ci-4alkyl;            and pharmaceutically acceptable addition salts, and solvates            thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), wherein

R¹ represents hydrogen or —C(═O)—C₁₋₄alkyl;R² represents hydrogen or —C(═O)—C₁₋₄alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, —CR^(5a)R⁵ ^(b) —X—,—C≡C—, —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, or —CR⁵ ^(a) R⁵^(b) C R⁵ ^(C) R^(5d)—CR⁵ ^(e) R^(5g)—CR^(5f)R^(5h)—.R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R⁵ ^(h) , andR⁵ ^(i) each independently represent hydrogen or Ci_₄alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH-Ci-4alkyl, and —N(Ci-₄alkyl)₂;Ar represents a monocyclic aromatic ring or a bicyclic ring system;wherein the monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;wherein the bicyclic ring system is

-   -   (i) a 9-membered bicyclic aromatic ring system consisting of a        6-membered ring fused with a 5-membered ring, containing one,        two or three heteroatoms each independently selected from O, S,        and N, said 9-membered bicyclic aromatic ring being attached to        the remainder of the molecule via a ring carbon atom of the 5-        or 6-membered ring, or a ring nitrogen atom of the 5-membered        ring; or    -   (ii) a 10-membered bicyclic aromatic ring system consisting of        two fused 6-membered rings, wherein optionally 1 or 2 ring        carbon atoms are replaced by a nitrogen atom; provided that when        the nitrogen atom replaces one of the two fused carbon atoms, a        carbonyl group is present in said bicyclic aromatic ring system;        -   provided that in case Ar represents a 10-membered bicyclic            aromatic ring system, Z can only represent            —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR⁵ ^(i) R⁵ ^(h) — or CR⁵ ^(a)            R⁵ ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —; or    -   (iii) a fused bicyclic partially aromatic ring system which is        attached with the aromatic ring to linker Z, wherein the fused        bicyclic partially aromatic ring system is selected from (b-1),        (b-2) and (b-3)

-   -   -   wherein ring A is a monocyclic aromatic ring is selected            from the group consisting of pyridinyl, pyrimidinyl,            pyrazolyl and imidazolyl;        -   wherein ring B is a C₅-ecycloalkyl or a 5- to 6-membered            saturated heterocyclyl containing one or two heteroatoms            each independently selected from O, S and N;            Ar is optionally substituted on the carbon atoms with in            total one, two, three or four substituents each            independently selected from the group consisting of halo,            oxo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃,            Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃_6 cycloalkyl,            C₂-₆alkenyl, Ci_₄alkyl, and            Ci_₄alkyl substituted with one Ci_₄alkyloxy; and            where possible Ar is optionally substituted on one N-atom            with one substituent selected from the group consisting of            Ci_₄alkyl; C₃-₆cycloalkyl; Ci_₄alkyl substituted with one,            two or three halo atoms; and C₃-₆cycloalkyl substituted with            one, two or three halo atoms;            R¹⁰ represents —(C=0)-Ci_₄alkyl; C₃-₆cycloalkyl; R¹⁴;            C₃-₆cycloalkyl substituted with one, two or three            substituents each independently selected from the group            consisting of halo, —OH and -0-Ci_₄alkyl; Ci_₄alkyl            substituted with one, two or three substituents each            independently selected from the group consisting of halo,            —OH and -0-Ci_₄alkyl; or Ci-₄alkyl substituted with one            substituent selected from the group consisting of            C₃-₆cycloalkyl, and R¹⁴;            R¹⁴ represents phenyl optionally substituted with one, two            or three substituents each independently selected from the            group consisting of halo;            Het represents a bicyclic aromatic heterocyclic ring system            selected from the group consisting of (a-1), (a-2) and            (a-3):

R³ ^(a) , R³ ^(d) and R³ ^(e) each independently represent hydrogen,halo, —NR⁷ ^(a) R^(7b), Ci_4 alkyl, C₂_4 alkenyl, C3-₆cycloalkyl, —OH,or -0-Ci-4alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, C3-₆cycloalkyl, or Ci-4alkyl;R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently representhydrogen, halo, —NR⁸ ^(a) R^(8b), or C₁₋₄alkyl;R⁸ ^(a) and R^(8b) each independently represent hydrogen or Ci-4alkyl;Q¹ represents N or CR⁶ ^(a) ;Q² represents N or CR^(6b);Q⁸ represents N or CR^(6g);Q⁹ represents N or CR^(6h);Q¹⁰ represents N or CR^(6i);Q¹¹ represents N or CR^(6j);Q⁵ represents CR^(3d); Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents CR^(3d); Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents N;R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each independentlyrepresent hydrogen, halogen, Ci_₄alkyl, —NR⁹ ^(a) R^(9b), or Ci-4alkylsubstituted with one, two or three halo atoms;R⁹ ^(a) and R^(9b) each independently represent hydrogen or Ci-4alkyl;

In an embodiment, the present invention concerns novel compounds ofFormula (I).

whereinR¹ represents hydrogen; R² represents hydrogen;Y represents —CH₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —,—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —, or—CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)—;R^(5a), R⁵ ^(b) R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R⁵ ^(h) , and R⁵^(i) each independently represent hydrogen or Ci-4alkyl;X represents -0-;Ar represents a monocyclic aromatic ring or a bicyclic ring system;wherein the monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;wherein the bicyclic ring system is

-   -   (i) a 9-membered bicyclic aromatic ring system consisting of a        6-membered ring fused with a 5-membered ring, containing one,        two or three heteroatoms each independently selected from O, S,        and N,        -   said 9-membered bicyclic aromatic ring being attached to the            remainder of the molecule via a ring carbon atom of the 5-            or 6-membered ring, or a ring nitrogen atom of the            5-membered ring; or    -   (ii) a 10-membered bicyclic aromatic ring system consisting of        two fused 6-membered rings, wherein 1 or 2 ring carbon atoms are        replaced by a nitrogen atom; provided that when the nitrogen        atom replaces one of the two fused carbon atoms, a carbonyl        group is present in said bicyclic aromatic ring system;        -   provided that in case Ar represents a 10-membered bicyclic            aromatic ring system, Z can only represent            —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) — or            _CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —;            _(or)    -   (iii) a fused bicyclic partially aromatic ring system which is        attached with the aromatic ring to linker Z, wherein the fused        bicyclic partially aromatic ring system is selected from (b-1)        and (b-3),        -   wherein ring A is pyridinyl;        -   wherein ring B is a 5- to 6-membered saturated heterocyclyl            containing one or two heteroatoms each independently            selected from O and N;            Ar is optionally substituted on the carbon atoms with in            total one, two, three or four substituents each            independently selected from the group consisting of halo,            oxo, —NH₂, —NH-Ci-4alkyl, —CF₃, C₃-₆cycloalkyl, and            Ci-4alkyl; and            where possible Ar is optionally substituted on one N-atom            with one Ci-4alkyl;            Het represents a bicyclic aromatic heterocyclic ring system            (a-1);            R³ ^(a) represents halo, —NR⁷ ^(a) R^(7b), or -0-Ci_₄alkyl;            R⁷ ^(a) represents hydrogen;            R^(7b) represents hydrogen or Ci-4alkyl;            R^(4a) represents hydrogen;            Q¹ represents CR⁶ ^(a) ;            Q² represents N or CR^(6b);            R⁶ ^(a) and R^(6b) each independently represent hydrogen or            halogen;            and pharmaceutically acceptable addition salts, and solvates            thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), wherein

R¹ represents hydrogen; R² represents hydrogen;Y represents —CH₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —,—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —, or —CR^(5a)R⁵ ^(b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —;R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), and R⁵^(i) each independently represent hydrogen or

Ci-4alkyl;

X represents -0-;Ar represents a monocyclic aromatic ring or a bicyclic ring system;wherein the monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;wherein the bicyclic ring system is

-   -   (i) a 9-membered bicyclic aromatic ring system consisting of a        6-membered ring fused with a 5-membered ring, containing one,        two or three heteroatoms each independently selected from O, S,        and N,        -   said 9-membered bicyclic aromatic ring being attached to the            remainder of the molecule via a ring carbon atom of the 5-            or 6-membered ring, or a ring nitrogen atom of the            5-membered ring; or    -   (ii) a 10-membered bicyclic aromatic ring system consisting of        two fused 6-membered rings, wherein 1 or 2 ring carbon atoms are        replaced by a nitrogen atom; provided that when the nitrogen        atom replaces one of the two fused carbon atoms, a carbonyl        group is present in said bicyclic aromatic ring system;        -   provided that in case Ar represents a 10-membered bicyclic            aromatic ring system, Z can only represent            —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) — or _CR^(5a)R⁵            ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —; or    -   (iii) a fused bicyclic partially aromatic ring system which is        attached with the aromatic ring to linker Z, wherein the fused        bicyclic partially aromatic ring system is selected from (b-1)        and (b-3),        -   wherein ring A is pyridinyl;        -   wherein ring B is a 5- to 6-membered saturated heterocyclyl            containing one or two heteroatoms each independently            selected from O and N;            Ar is optionally substituted on the carbon atoms with in            total one, two, three or four substituents each            independently selected from the group consisting of halo,            oxo, —NH₂, —NH-Ci-4alkyl, —CF3, C3_₆cycloalkyl, and            Ci-4alkyl; and            where possible Ar is optionally substituted on one N-atom            with one Ci-4alkyl;            Het represents a bicyclic aromatic heterocyclic ring system            (a-1);            R³ ^(a) represents halo, —NR ⁷ ^(a) R^(7b), or —O-Ci_₄alkyl;            R⁷ ^(a) represents hydrogen;            R^(7b) represents hydrogen or Ci-₄alkyl;            R^(4a) represents hydrogen;            Q¹ represents CR⁶ ^(a) ;            Q² represents CR^(6b);            R⁶ ^(a) and R^(6b) each independently represent hydrogen or            halogen;            and pharmaceutically acceptable addition salts, and solvates            thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I).

R¹ represents hydrogen; R² represents hydrogen;Y represents —CH2-;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —,—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —, or —CR^(5a)R⁵ ^(b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R⁵ ^(h) , andR⁵ ^(i) each independently represent hydrogen or Ci-₄alkyl;X represents -0-;Ar represents a monocyclic aromatic ring or a bicyclic ring system;wherein the monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;wherein the bicyclic ring system is

-   -   (i) a 9-membered bicyclic aromatic ring system consisting of a        6-membered ring fused with a 5-membered ring, containing one,        two or three heteroatoms each independently selected from O, S,        and N,        -   said 9-membered bicyclic aromatic ring being attached to the            remainder of the molecule via a ring carbon atom of the 5-            or 6-membered ring, or a ring nitrogen atom of the            5-membered ring; or    -   (ii) a 10-membered bicyclic aromatic ring system consisting of        two fused 6-membered rings, wherein 1 or 2 ring carbon atoms are        replaced by a nitrogen atom; provided that when the nitrogen        atom replaces one of the two fused carbon atoms, a carbonyl        group is present in said bicyclic aromatic ring system;        -   provided that in case Ar represents a 10-membered bicyclic            aromatic ring system, Z can only represent            —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) — or _CR^(5a)R⁵            ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —; or    -   (iii) a fused bicyclic partially aromatic ring system which is        attached with the aromatic ring to linker Z, wherein the fused        bicyclic partially aromatic ring system is selected from (b-1)        and (b-3),        -   wherein ring A is pyridinyl;        -   wherein ring B is a 5- to 6-membered saturated heterocyclyl            containing one or two heteroatoms each independently            selected from 0 and N;            Ar is optionally substituted on the carbon atoms with in            total one, two, three or four substituents each            independently selected from the group consisting of halo,            oxo, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, —CF₃, C₃-₆cycloalkyl, and            Ci_₄alkyl; and            where possible Ar is optionally substituted on one N-atom            with one Ci_₄alkyl;            R¹⁰ represents —(C=0)-Ci_₄alkyl;            Het represents a bicyclic aromatic heterocyclic ring system            (a-1);            R³ ^(a) represents halo, —NR⁷ ^(a) R^(7b), or -0-Ci_₄alkyl;            R⁷ ^(a) represents hydrogen;            R^(7b) represents hydrogen or Ci_₄alkyl;            R^(4a) represents hydrogen;            Q¹ represents CR⁶ ^(a) ;            Q² represents CR^(6b);            R⁶ ^(a) and R^(6b) each independently represent hydrogen or            halogen;            and pharmaceutically acceptable addition salts, and solvates            thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I),

whereinR¹ represents hydrogen or —C(=0)-Ci_₄alkyl;R² represents hydrogen or —C(=0)-Ci_₄alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, —CR^(5a)R⁵ ^(b) —X—,—C≡C—, —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, or—CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R^(5h)—.R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R⁵ ^(h) , and R⁵^(i) each independently represent hydrogen or Ci_₄alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH-Ci-4alkyl, and —N(Ci-₄alkyl)₂;Ar represents a monocyclic aromatic ring selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, oxo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃,Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃_6 cycloalkyl, C₂-₆alkenyl,Ci-4alkyl, andCi_4alkyl substituted with one Ci-4alkyloxy; andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci-4alkyl;C₃-₆cycloalkyl; Ci-4alkyl substituted with one, two or three halo atoms;and C₃-₆cycloalkyl substituted with one, two or three halo atoms;R¹⁰ represents —(C=0)-Ci_4 alkyl; C₃-₆cycloalkyl; R¹⁴; C₃-₆cycloalkylsubstituted with one, two or three substituents each independentlyselected from the group consisting of halo, —OH and -0-Ci-4alkyl;Ci-4alkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and-0-Ci-4alkyl; or Ci-4alkyl substituted with one substituent selectedfrom the group consisting of C₃₋₆cycloalkyl, and R¹⁴;R¹⁴ represents phenyl optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo;Het represents a bicyclic aromatic heterocyclic ring system selectedfrom the group consisting of (a-1), (a-2) and (a-3);R³ ^(a) , R³ ^(d) and R^(3e) each independently represent hydrogen,halo, —NR⁷ ^(a) R^(7b), Ci_4 alkyl, C₂_4 alkenyl, C₃-₆cycloalkyl, —OH,or -0-Ci-4alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, C₃-₆cycloalkyl, or Ci-4alkyl;R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently representhydrogen, halo, —NR⁸ ^(a) R^(8b), or Ci₋₄alkyl;R⁸ ^(a) and R^(8b) each independently represent hydrogen or Ci-4alkyl;Q¹ represents N or CR⁶ ^(a) ;Q² represents N or CR^(6b);Q⁸ represents N or CR^(6g);Q⁹ represents N or CR^(6h);Q¹⁰ represents N or CR^(6i);Q¹¹ represents N or CR^(6j);Q⁵ represents CR³ ^(d) ; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents CR³ ^(d) ; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents N;R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each independentlyrepresent hydrogen, halogen, Ci_₄alkyl, —NR⁹ ^(a) R^(9b), or Ci-4alkylsubstituted with one, two or three halo atoms;R⁹ ^(a) and R^(9b) each independently represent hydrogen or Ci-4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I).

whereinR¹ represents hydrogen or —C(═O)—C₁₋₄ alkyl;R² represents hydrogen or —C(═O)—C₁₋₄ alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, —CR^(5a)R⁵ ^(b) —X—,—C≡C—, —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, or —CR^(5a)R⁵ ^(b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —.R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R⁵ ^(h) , and R⁵^(i) each independently represent hydrogen or Ci-4alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH-Ci-4alkyl, and —N(Ci-₄alkyl)₂;Ar represents a bicyclic ring system; wherein the bicyclic ring systemis

-   -   (i) a 9-membered bicyclic aromatic ring system consisting of a        6-membered ring fused with a 5-membered ring, containing one,        two or three heteroatoms each independently selected from O, S,        and N,        -   said 9-membered bicyclic aromatic ring being attached to the            remainder of the molecule via a ring carbon atom of the 5-            or 6-membered ring, or a ring nitrogen atom of the            5-membered ring; or    -   (ii) a 10-membered bicyclic aromatic ring system consisting of        two fused 6-membered rings, wherein optionally 1 or 2 ring        carbon atoms are replaced by a nitrogen atom; provided that when        the nitrogen atom replaces one of the two fused carbon atoms, a        carbonyl group is present in said bicyclic aromatic ring system;        -   provided that in case Ar represents a 10-membered bicyclic            aromatic ring system, Z can only represent            —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) — or            _CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) -;            or    -   (iii) a fused bicyclic partially aromatic ring system which is        attached with the aromatic ring to linker Z, wherein the fused        bicyclic partially aromatic ring system is selected from (b-1),        (b-2) and (b-3)

-   -   -   wherein ring A is a monocyclic aromatic ring is selected            from the group consisting of pyridinyl, pyrimidinyl,            pyrazolyl and imidazolyl;        -   wherein ring B is a C₅-ecycloalkyl or a 5- to 6-membered            saturated heterocyclyl containing one or two heteroatoms            each independently selected from O, S and N;            Ar is optionally substituted on the carbon atoms with in            total one, two, three or four substituents each            independently selected from the group consisting of halo,            oxo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃,            Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃_6 cycloalkyl,            C₂-₆alkenyl, Ci_₄alkyl, and            Ci_₄alkyl substituted with one Ci_₄alkyloxy; and            where possible Ar is optionally substituted on one N-atom            with one substituent selected from the group consisting of            Ci_₄alkyl; C₃-₆cycloalkyl; Ci_₄alkyl substituted with one,            two or three halo atoms; and C₃-₆cycloalkyl substituted with            one, two or three halo atoms;            R¹⁰ represents —(C=0)-Ci_₄alkyl; C₃-₆cycloalkyl; R¹⁴;            C₃-₆cycloalkyl substituted with one, two or three            substituents each independently selected from the group            consisting of halo, —OH and -0-Ci_₄alkyl; Ci_₄alkyl            substituted with one, two or three substituents each            independently selected from the group consisting of halo,            —OH and -0-Ci_₄alkyl; or Ci-₄alkyl substituted with one            substituent selected from the group consisting of            C₃₋₆cycloalkyl, and R¹⁴;            R¹⁴ represents phenyl optionally substituted with one, two            or three substituents each independently selected from the            group consisting of halo;            Het represents a bicyclic aromatic heterocyclic ring system            selected from the group consisting of (a-1), (a-2) and            (a-3);            R³ ^(a) , R³ ^(d) and R^(3e) each independently represent            hydrogen, halo, —NR⁷ ^(a) R^(7b), Ci_4alkyl, C₂_4alkenyl,            C3-₆cycloalkyl, —OH, or -0-Ci-4alkyl;            R⁷ ^(a) represents hydrogen;            R^(7b) represents hydrogen, C3_₆cycloalkyl, or Ci-4alkyl;            R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently            represent hydrogen, halo, —NR⁸ ^(a) R^(8b), or Ci_₄alkyl;            R⁸ ^(a) and R^(8b) each independently represent hydrogen or            Ci-4alkyl;            Q¹ represents N or CR⁶ ^(a) ;            Q² represents N or CR^(6b);            Q⁸ represents N or CR^(6g);            Q⁹ represents N or CR^(6h);            Q¹⁰ represents N or CR^(6i);            Q¹¹ represents N or CR^(6j);            Q⁵ represents CR³ ^(d) ; Q⁶ represents N; and Q⁷ represents            CR^(4f); or            Q⁵ represents CR³ ^(d) ; Q⁶ represents CR^(4e); and Q⁷            represents N; or            Q⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents            CR^(4f); or            Q⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N;            or            Q⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f);            or            Q⁵ represents N; Q⁶ represents N; and Q⁷ represents N;            R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each            independently represent hydrogen, halogen, Ci_4alkyl, —NR⁹            ^(a) R^(9b), or Ci-4alkyl substituted with one, two or three            halo atoms;            R⁹ ^(a) and R^(9b) each independently represent hydrogen or            Ci-4alkyl;            and pharmaceutically acceptable addition salts, and solvates            thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I).

whereinR¹ represents hydrogen or —C(=0)-Ci_4alkyl;R² represents hydrogen or —C(=0)-Ci_4alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R^(5h)—, —CR^(5a)R^(5b)—X—,—C≡C—, CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, or—CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R^(5h)—;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R⁵ ^(h) , andR⁵ ^(i) each independently represent hydrogen or Ci-4alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH-Ci-4alkyl, and —N(Ci-₄alkyl)₂;Ar represents a fused bicyclic partially aromatic ring system which isattached with the aromatic ring to linker Z, wherein the fused bicyclicpartially aromatic ring system is selected from (b-1), (b-2) and (b-3)

-   -   wherein ring A is a monocyclic aromatic ring is selected from        the group consisting of pyridinyl, pyrimidinyl, pyrazolyl and        imidazolyl;    -   wherein ring B is a C₅-ecycloalkyl or a 5- to 6-membered        saturated heterocyclyl containing one or two heteroatoms each        independently selected from O, S and N;        Ar is optionally substituted on the carbon atoms with in total        one, two, three or four substituents each independently selected        from the group consisting of halo, oxo, —OH, —NH₂,        —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃, Ci_₄alkyloxy,        C₃-₆cycloalkyl, -0-C₃_6 cycloalkyl, C₂-₆alkenyl, Ci-4alkyl, and        Ci_4 alkyl substituted with one Ci-4alkyloxy; and        where possible Ar is optionally substituted on one N-atom with        one substituent selected from the group consisting of Ci-4alkyl;        C₃-₆cycloalkyl; Ci-4alkyl substituted with one, two or three        halo atoms; and C₃-₆cycloalkyl substituted with one, two or        three halo atoms;        R¹⁰ represents —(C=0)-Ci_4 alkyl; C₃-₆cycloalkyl; R¹⁴;        C₃-₆cycloalkyl substituted with one, two or three substituents        each independently selected from the group consisting of halo,        —OH and -0-Ci-4alkyl; Ci-4alkyl substituted with one, two or        three substituents each independently selected from the group        consisting of halo, —OH and -0-Ci-4alkyl; or Ci-4alkyl        substituted with one substituent selected from the group        consisting of C₃₋₆cycloalkyl, and R¹⁴;        R¹⁴ represents phenyl optionally substituted with one, two or        three substituents each independently selected from the group        consisting of halo;        Het represents a bicyclic aromatic heterocyclic ring system        selected from the group consisting of (a-1), (a-2) and (a-3);        R³ ^(a) , R³ ^(d) and R^(3e) each independently represent        hydrogen, halo, —NR⁷ ^(a) R^(7b), Ci_4 alkyl, C₂_4 alkenyl,        C₃-₆cycloalkyl, —OH, or -0-Ci-4alkyl;        R^(7a) represents hydrogen;        R^(7b) represents hydrogen, C3-₆cycloalkyl, or Ci-4alkyl;        R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently        represent hydrogen, halo, —NR⁸ ^(a) R^(8b), or Ci_₄alkyl;        R⁸ ^(a) and R^(8b) each independently represent hydrogen or        Ci-₄alkyl;        Q¹ represents N or CR⁶ ^(a) ;        Q² represents N or CR^(6b);        Q⁸ represents N or CR^(6g);        Q⁹ represents N or CR^(6h);        Q¹⁰ represents N or CR^(6i);        Q¹¹ represents N or CR^(6j);        Q⁵ represents CR³ ^(d) ; Q⁶ represents N; and Q⁷ represents        CR^(4f); or        Q⁵ represents CR³ ^(d) ; Q⁶ represents CR^(4e); and Q⁷        represents N; or        Q⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents        CR^(4f); or        Q⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N; or        Q⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f); or        Q⁵ represents N; Q⁶ represents N; and Q⁷ represents N;        R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each        independently represent hydrogen, halogen, Ci_₄alkyl, —NR⁹ ^(a)        R^(9b), or Ci-₄alkyl substituted with one, two or three halo        atoms;        R⁹ ^(a) and R^(9b) each independently represent hydrogen or        Ci-4alkyl;        and pharmaceutically acceptable addition salts, and solvates        thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I).

whereinR¹ represents hydrogen or —C(=0)-Ci_₄alkyl;R² represents hydrogen or —C(=0)-Ci_₄alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R^(5h)—, —CR^(5a)R⁵ ^(b) —X—,—C≡C—, CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, or -CR^(5a)R⁵ ^(b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R⁵ ^(h) , andR⁵ ^(i) each independently represent hydrogen or Ci-₄alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci-₄alkyl, or Ci-₄alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-₄alkyl,—NH₂, —NH-Ci-₄alkyl, and —N(Ci-₄alkyl)₂;Ar represents a 9-membered bicyclic aromatic ring system consisting of a6-membered ring fused with a 5-membered ring, containing one, two orthree heteroatoms each independently selected from O, S, and N,said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, oxo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃,Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃_6 cycloalkyl, C₂-₆alkenyl,Ci_₄alkyl, andCi_₄alkyl substituted with one Ci_₄alkyloxy; andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci_₄alkyl;C₃-₆cycloalkyl; Ci_₄alkyl substituted with one, two or three halo atoms;and C₃-₆cycloalkyl substituted with one, two or three halo atoms;R¹⁰ represents —(C=0)-Ci_₄alkyl; C₃-₆cycloalkyl; R¹⁴; C₃-₆cycloalkylsubstituted with one, two or three substituents each independentlyselected from the group consisting of halo, —OH and -0-Ci_₄alkyl;Ci_₄alkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and-0-Ci_₄alkyl; or Ci-₄alkyl substituted with one substituent selectedfrom the group consisting of C₃₋₆cycloalkyl, and R¹⁴;R¹⁴ represents phenyl optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo;Het represents a bicyclic aromatic heterocyclic ring system selectedfrom the group consisting of (a-1), (a-2) and (a-3);R³ ^(a) , R³ ^(d) and R^(3e) each independently represent hydrogen,halo, —NR⁷ ^(a) R^(7b), Ci_₄ alkyl, C₂₋₄ alkenyl, C₃-₆cycloalkyl, —OH,or -0-Ci_₄alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, C₃-₆cycloalkyl, or Ci_₄alkyl;R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently representhydrogen, halo, —NR⁸ ^(a) R^(8b), or Ci_₄alkyl;R⁸ ^(a) and R^(8b) each independently represent hydrogen or Ci-₄alkyl;Q¹ represents N or CR⁶ ^(a) ;Q² represents N or CR^(6b);Q⁸ represents N or CR^(6g);Q⁹ represents N or CR^(6h);Q¹⁰ represents N or CR^(6i);Q¹¹ represents N or CR^(6j);Q⁵ represents CR³ ^(d) ; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents CR³ ^(d) ; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents N;R^(6a), R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each independentlyrepresent hydrogen, halogen, Ci_₄alkyl, —NR⁹ ^(a) R^(9b), or Ci-4alkylsubstituted with one, two or three halo atoms;R⁹ ^(a) and R^(9b) each independently represent hydrogen or Ci-4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I),

whereinR¹ represents hydrogen or —C(═O)—C₁₋₄alkyl;R² represents hydrogen or —C(═O)—C₁₋₄alkyl;Y represents —CH₂— or —CF₂—;Z represents —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, or—CR^(5a)R⁵ ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), and R⁵^(i) each independently represent hydrogen or Ci_4alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH—C₁₋₄alkyl, and —N(Ci-₄alkyl)₂;Ar represents a 10-membered bicyclic aromatic ring system consisting oftwo fused 6-membered rings, wherein optionally 1 or 2 ring carbon atomsare replaced by a nitrogen atom; provided that when the nitrogen atomreplaces one of the two fused carbon atoms, a carbonyl group is presentin said bicyclic aromatic ring system;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, oxo, —OH, —NH₂, —NH—Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃,Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃_6 cycloalkyl, C₂-₆alkenyl,Ci-4alkyl, andCi_4 alkyl substituted with one Ci-4alkyloxy; andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci-4alkyl;C₃-₆cycloalkyl; Ci-4alkyl substituted with one, two or three halo atoms;and C₃_6 cycloalkyl substituted with one, two or three halo atoms;R¹⁰ represents —(C=0)-Ci-4alkyl; C₃_6cycloalkyl; R¹⁴; C₃_6cycloalkylsubstituted with one, two or three substituents each independentlyselected from the group consisting of halo, —OH and -0-Ci-4alkyl;Ci-4alkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and-0-Ci-4alkyl; or Ci-4alkyl substituted with one substituent selectedfrom the group consisting of C₃-₆cycloalkyl, and R¹⁴;R¹⁴ represents phenyl optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo;Het represents a bicyclic aromatic heterocyclic ring system selectedfrom the group consisting of (a-1), (a-2) and (a-3):R³ ^(a) , R³ ^(d) and R^(3e) each independently represent hydrogen,halo, —NR⁷ ^(a) R^(7b), Ci_4 alkyl, C₂_4 alkenyl, C₃_6cycloalkyl, —OH,or -0-Ci-4alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, C₃-₆cycloalkyl, or Ci-4alkyl;R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently representhydrogen, halo, —NR⁸ ^(a) R^(8b), or Ci_₄alkyl;R⁸ ^(a) and R^(8b) each independently represent hydrogen or Ci-4alkyl;Q¹ represents N or CR⁶ ^(a) ;Q² represents N or CR^(6b);Q⁸ represents N or CR^(6g);Q⁹ represents N or CR^(6h);Q¹⁰ represents N or CR^(6i);Q¹¹ represents N or CR⁶ ^(j) ;Q⁵ represents CR³ ^(d) ; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents CR³ ^(d) ; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents N;R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each independentlyrepresent hydrogen, halogen, Ci_4alkyl, —NR⁹ ^(a) R^(9b), or Ci-4alkylsubstituted with one, two or three halo atoms;R⁹ ^(a) and R^(9b) each independently represent hydrogen or Ci-4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I).

whereinR¹ represents hydrogen;R² represents hydrogen;Y represents —CH₂;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, —CR^(5a)R⁵ ^(b) —X—,—C≡C—, —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R^(5h)—, or—CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R^(5h)—.R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R⁵ ^(h) , andR⁵ ^(i) each independently represent hydrogen or Ci-₄alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci-₄alkyl, or Ci-₄alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci_₄alkyl,—NH₂, —NH-Ci_₄alkyl, and —N(Ci_₄alkyl)₂;Ar represents a monocyclic aromatic ring or a bicyclic ring system;wherein the monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl;wherein the bicyclic ring system is

-   -   (i) a 9-membered bicyclic aromatic ring system consisting of a        6-membered ring fused with a 5-membered ring, containing one,        two or three heteroatoms each independently selected from O, S,        and N,        -   said 9-membered bicyclic aromatic ring being attached to the            remainder of the molecule via a ring carbon atom of the 5-            or 6-membered ring, or a ring nitrogen atom of the            5-membered ring; or    -   (ü) a 10-membered bicyclic aromatic ring system consisting of        two fused 6-membered rings, wherein optionally 1 or 2 ring        carbon atoms are replaced by a nitrogen atom; provided that when        the nitrogen atom replaces one of the two fused carbon atoms, a        carbonyl group is present in said bicyclic aromatic ring system;        -   provided that in case Ar represents a 10-membered bicyclic            aromatic ring system, Z can only represent            —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)— or _CR^(5a)R⁵            ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —; or    -   (iii) a fused bicyclic partially aromatic ring system which is        attached with the aromatic ring to linker Z, wherein the fused        bicyclic partially aromatic ring system is selected from (b-1),        (b-2) and (b-3)

-   -   -   wherein ring A is a monocyclic aromatic ring is selected            from the group consisting of pyridinyl, pyrimidinyl,            pyrazolyl and imidazolyl;        -   wherein ring B is a C₅-ecycloalkyl or a 5- to 6-membered            saturated heterocyclyl containing one or two heteroatoms            each independently selected from O, S and N;            Ar is optionally substituted on the carbon atoms with in            total one, two, three or four substituents each            independently selected from the group consisting of halo,            oxo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃,            Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃_6cycloalkyl,            C₂-₆alkenyl, Ci_₄alkyl, and            Ci_₄alkyl substituted with one Ci_₄alkyloxy; and            where possible Ar is optionally substituted on one N-atom            with one substituent selected from the group consisting of            Ci_₄alkyl; C₃-₆cycloalkyl; Ci_₄alkyl substituted with one,            two or three halo atoms; and C₃-₆cycloalkyl substituted with            one, two or three halo atoms;            R¹⁰ represents —(C=0)-Ci_₄alkyl; C₃-₆cycloalkyl; R¹³; R¹⁴;            C₃-₆cycloalkyl substituted with one, two or three            substituents each independently selected from the group            consisting of halo, —OH and -0-Ci_₄alkyl; Ci_₄alkyl            substituted with one, two or three substituents each            independently selected from the group consisting of halo,            —OH and -0-Ci_₄alkyl; or Ci_₄alkyl substituted with one            substituent selected from the group consisting of C₃_6            cycloalkyl, R¹³ and R¹⁴;            R¹³ represents a 4- to 7-membered monocyclic aromatic ring            containing one, two or three heteroatoms each independently            selected from O, S, S(=0)_(p) and N; said 4- to 7-membered            monocyclic aromatic ring is optionally substituted with one            or two substituents selected from the group consisting of            Ci_₄alkyl;            p represents 1 or 2;            R¹⁴ represents phenyl optionally substituted with one, two            or three substituents each independently selected from the            group consisting of halo;            Het represents a bicyclic aromatic heterocyclic ring system            (a-1);            R³ ^(a) represents -NR⁷ ^(a) R^(7b);            R^(7a) represents hydrogen; R^(7b) represents hydrogen;            R^(4a) represents hydrogen;            Q¹ represents CR⁶ ^(a) ; Q² represents CR^(6b);            R^(5a) and R^(5b) represent hydrogen;            and pharmaceutically acceptable addition salts, and solvates            thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I),

whereinR¹ represents hydrogen or —C(═O)—C₁₋₄alkyl;R² represents hydrogen or —C(═O)—C₁₋₄alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —X—CR^(5a)CR⁵ ^(b) —, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, —CR^(5a)R⁵ ^(b) —X—, or —C≡C—;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), and R^(5h)each independently represent hydrogen or Ci_₄alkyl;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH-Ci-4alkyl, and —N(Ci-₄alkyl)₂;Ar represents a monocyclic aromatic ring selected from pyridinyl andimidazolyl;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃,Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃-₆cycloalkyl, C₂-₆alkenyl, Ci-4alkyl,and Ci-4alkyl substituted with one Ci-4alkyloxy;R¹⁰ represents —(C=0)-Ci-4alkyl; C₃-₆cycloalkyl; R¹³; R¹⁴;C₃-₆cycloalkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and-0-Ci-4alkyl; Ci-4alkyl substituted with one, two or three substituentseach independently selected from the group consisting of halo, —OH and-0-Ci_4 alkyl; or Ci-4alkyl substituted with one substituent selectedfrom the group consisting of C₃_6 cycloalkyl, R¹³ and R¹⁴;R¹³ represents a 4- to 7-membered monocyclic aromatic ring containingone, two or three heteroatoms each independently selected from O, S,S(=0)_(p) and N; said 4- to 7-membered monocyclic aromatic ring isoptionally substituted with one or two substituents selected from thegroup consisting of Ci-4alkyl;p represents 1 or 2;R¹⁴ represents phenyl optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo;Het represents a bicyclic aromatic heterocyclic ring system selectedfrom the group consisting of (a-1), (a-2) and (a-3);R³ ^(a) , R³ ^(d) and R^(3e) each independently represent hydrogen,halo, —NR⁷ ^(a) R^(7b), Ci_4 alkyl, C₂_4 alkenyl, C3-₆cycloalkyl, —OH,or -0-Ci-4alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, C3-₆cycloalkyl, or Ci-4alkyl;R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently representhydrogen, halo, —NR⁸ ^(a) R^(8b), or C₁₋₄alkyl;R⁸ ^(a) and R^(8b) each independently represent hydrogen or Ci-4alkyl;Q¹ represents N or CR⁶ ^(a) ;Q² represents N or CR^(6b);Q⁸ represents N or CR^(6g);Q⁹ represents N or CR^(6h);Q¹⁰ represents N or CR^(6i);Q¹¹ represents N or CR^(6j);Q⁵ represents CR³ ^(d) ; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents CR^(3d); Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents N;R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each independentlyrepresent hydrogen, halogen, Ci_₄alkyl, —NR⁹ ^(a) R^(9b), or Ci-4alkylsubstituted with one, two or three halo atoms;R⁹ ^(a) and R^(9b) each independently represent hydrogen or Ci-4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I).

whereinR¹ represents hydrogen or —C(=0)-Ci_4alkyl;R² represents hydrogen or —C(=0)-Ci_4alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, —CR^(5a)R⁵ ^(b) —X—, or —C≡C—;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), and R^(5h)each independently represent hydrogen or Ci_4alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH-Ci-4alkyl, and —N(Ci-₄alkyl)₂;Ar represents a 9-membered bicyclic aromatic ring system consisting of a6-membered ring fused with a 5-membered ring, containing one, two orthree heteroatoms each independently selected from O, S, and N,said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —OH, —NH₂, —NH—C₁₋₄alkyl, —NHR¹⁰, cyano, —CF₃,Ci-4alkyloxy, C₃-ecycloalkyl, -0-C₃-ecycloalkyl, C₂-6alkenyl, Ci-4alkyl,and Ci-4alkyl substituted with one Ci-4alkyloxy; andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci-4alkyl;C₃-₆cycloalkyl; Ci-4alkyl substituted with one, two or three halo atoms;and C₃-₆cycloalkyl substituted with one, two or three halo atoms;R¹⁰ represents —(C═O)—C₁₋₄alkyl; C₃-₆cycloalkyl; R¹³; R¹⁴;C₃-₆cycloalkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and-0-Ci-4alkyl; Ci-4alkyl substituted with one, two or three substituentseach independently selected from the group consisting of halo, —OH and-0-Ci_4 alkyl; or Ci-4alkyl substituted with one substituent selectedfrom the group consisting of C₃_6 cycloalkyl, R¹³ and R¹⁴;R¹³ represents a 4- to 7-membered monocyclic aromatic ring containingone, two or three heteroatoms each independently selected from O, S,S(=0)_(p) and N; said 4- to 7-membered monocyclic aromatic ring isoptionally substituted with one or two substituents selected from thegroup consisting of Ci-4alkyl;p represents 1 or 2;R¹⁴ represents phenyl optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo;Het represents a bicyclic aromatic heterocyclic ring system selectedfrom the group consisting of (a-1), (a-2) and (a-3);R³ ^(a) , R³ ^(d) and R^(3e) each independently represent hydrogen,halo, —NR⁷ ^(a) R^(7b), Ci_4 alkyl, C₂-4 alkenyl, C₃-₆cycloalkyl, —OH,or -0-Ci-4alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, C₃-₆cycloalkyl, or Ci-4alkyl;R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently representhydrogen, halo, —NR⁸ ^(a) R^(8b), or Ci_₄alkyl;R⁸ ^(a) and R^(8b) each independently represent hydrogen or Ci-4alkyl;Q¹ represents N or CR⁶ ^(a) ;Q² represents N or CR^(6b);Q⁸ represents N or CR^(6g);Q⁹ represents N or CR^(6h);Q¹⁰ represents N or CR^(6i);Q¹¹ represents N or CR^(6j);Q⁵ represents CR³ ^(d) ; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents CR³ ^(d) ; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents N;R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each independentlyrepresent hydrogen, halogen, Ci_₄alkyl, —NR⁹ ^(a) R^(9b), or Ci-4alkylsubstituted with one, two or three halo atoms;R⁹ ^(a) and R^(9b) each independently represent hydrogen or Ci-4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I),

whereinR¹ represents hydrogen or —C(=0)-Ci-4alkyl;R² represents hydrogen or —C(═O)—C₁₋₄ alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —X—CR^(5a)R^(5b)—, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, —CR^(5a)R^(5b)—X—, or —C≡C—;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), Rye, R^(5f), R^(5g), and R^(5h) eachindependently represent hydrogen or Ci_4alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci-4alkyl,—NH₂, —NH-Ci-4alkyl, and —N(Ci-₄alkyl)₂;Ar represents a monocyclic aromatic ring selected from pyridinyl andimidazolyl; or a 9-membered bicyclic aromatic ring system consisting ofa 6-membered ring fused with a 5-membered ring, containing one, two orthree heteroatoms each independently selected from O, S, and N,said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —OH, —NH₂, —NH-Ci_₄alkyl,—NHR¹⁰, cyano, —CF3, Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C3-6cycloalkyl,C₂₋₆alkenyl, Ci_₄alkyl, and Ci_₄alkyl substituted with one Ci_₄alkyloxy;andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci_₄alkyl;C3-₆cycloalkyl; Ci_₄alkyl substituted with one, two or three halo atoms;and C3-₆cycloalkyl substituted with one, two or three halo atoms;R¹⁰ represents —(C=0)-Ci_₄alkyl; C3-₆cycloalkyl; C3-₆cycloalkylsubstituted with one, two or three substituents each independentlyselected from the group consisting of halo, —OH and -0-Ci_₄alkyl;Ci_₄alkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and—O-Ci_₄alkyl; or Ci_₄alkyl substituted with one C3-6cycloalkyl;Het represents a bicyclic aromatic heterocyclic ring system selectedfrom the group consisting of (a-1), (a-2) and (a-3):

R^(3a), R³ ^(d) and R^(3e) each independently represent hydrogen, halo,—NR^(7a)R^(7b), Ci_₄alkyl, C₂-₄alkenyl, C3-₆cycloalkyl, —OH, or-0-Ci_₄alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, C3-₆cycloalkyl, or Ci_₄alkyl;R^(4a), R^(4d), R^(4e), R^(4f)and R^(4g) each independently representhydrogen, halo, —NR⁸ ^(a) R^(8b), or Ci_₄alkyl;R⁸ ^(a) and R^(8b) each independently represent hydrogen or Ci-₄alkyl;Q¹ represents CR⁶ ^(a) ;Q² represents CR^(6b);Q⁸ represents CR^(6g);Q⁹ represents CR^(6h);Q¹⁰ represents CR^(6i);Q¹¹ represents CR^(6j);Q⁵ represents CR³ ^(d) ; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents CR³ ^(d) ; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents N;R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each independentlyrepresent hydrogen, halogen, Ci_₄alkyl, —NR⁹ ^(a) R^(9b), or Ci-4alkylsubstituted with one, two or three halo atoms;R⁹ ^(a) and R^(9b) each independently represent hydrogen or Ci-4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I),

whereinR¹ represents hydrogen;R² represents hydrogen;Y represents —CH₂;Z represents —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—, or—CR^(5e)R^(5g)—CR^(5f)R^(5h)—;R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), and R^(5h)represent hydrogen;X represents -0-;Ar represents a monocyclic aromatic ring selected from pyridinyl andimidazolyl; or a 9-membered bicyclic aromatic ring system consisting ofa 6-membered ring fused with a 5-membered ring, containing one, two orthree heteroatoms each independently selected from O, S, and N,said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —NH₂, —NH-Ci-4alkyl, —CF₃, C₃-6cycloalkyl, andCi-4alkyl; andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci-4alkyl;Het represents (a-1);R^(3a) represents halo, —NR⁷ ^(a) R^(7b), or -0-Ci_₄alkyl;R^(7a) represents hydrogen;R^(7b) represents hydrogen, or Ci-4alkyl;R^(4a) represents hydrogen;Q¹ represents CR⁶ ^(a) ;Q² represents CR^(6b);R⁶ ^(a) and R^(6b) represent hydrogen, or halogen;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I).

whereinR¹ represents hydrogen;R² represents hydrogen;Y represents —CH₂—;Z represents —X—CR^(5a)R^(5b)—, —CR^(5c)═CR^(5d)—, or—CR^(5e)R^(5g)—CR^(5f)R^(5h)—;R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), and R^(5h)represent hydrogen;X represents -0-;Ar represents a monocyclic aromatic ring selected from pyridinyl andimidazolyl; or a 9-membered bicyclic aromatic ring system selected fromthe group consisting of

Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —NH₂, —NH-Ci_4 alkyl, —CF₃, C₃-₆cycloalkyl, andCi-4alkyl; andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci-4alkyl;Het represents (a-1);R^(3a) represents halo, —NR⁷ ^(a) R^(7b), or -0-Ci_₄alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, or Ci-₄alkyl;R^(4a) represents hydrogen;Q¹ represents CR⁶ ^(a) ;Q² represents CR^(6b);R^(6a) and R^(6b) represent hydrogen, or halogen;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I),

whereinR¹ represents hydrogen;R² represents hydrogen;Y represents —CH₂—;Z represents —CR^(5e)R^(5g)—CR^(5i)R^(5h)—;R^(5e), R^(5f), R^(5g), and R^(5h) represent hydrogen;Ar represents

Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —NH₂, —NH-Ci_4 alkyl, —CF₃, C₃-₆cycloalkyl, andCi-4alkyl;Het represents (a-1);R³ ^(a) represents —NR⁷ ^(a) R^(7h);R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen;R^(4a) represents hydrogen;Q¹ represents CR⁶ ^(a) ;Q² represents CR^(6b);R⁶ ^(a) and R^(6b) represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I),

whereinR¹ represents hydrogen;R² represents hydrogen;Y represents —CH₂—;Z represents —CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —;R^(5e), R^(5f), R^(5g), and R⁵ ^(h) represent hydrogen;Ar represents

wherein Ar is substituted in the position indicated by β with G-₄alkyl;wherein Ar is optionally substituted in the position indicated by γ withhalo;Het represents (a-1);R^(3a) represents —NR⁷ ^(a) R^(7b);R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen;R^(4a) represents hydrogen;Q¹ represents CR⁶ ^(a) ;Q² represents CR^(6b);R⁶ ^(a) and R^(6b) represent hydrogen;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I),

whereinR¹ represents hydrogen; R² represents hydrogen;Y represents —CH₂— or —CF₂—;Z represents-CH₂—, —X—CR^(5a)R^(5b)—, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, —CR^(5a)R⁵ ^(b) —X—, or —C≡C—;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), Rye, R^(5f), R^(5g), and R^(5h) eachindependently represent hydrogen or Ci_₄alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci_₄alkyl, or Ci_₄alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci_₄alkyl,—NH₂, —NH-Ci_₄alkyl, and —N(Ci_₄alkyl)₂;Ar represents a monocyclic aromatic ring selected from pyridinyl andimidazolyl; or a 9-membered bicyclic aromatic ring system consisting ofa 6-membered ring fused with a 5-membered ring, containing one, two orthree heteroatoms each independently selected from O, S, and N,said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —OH, —NH₂, —NH-Ci_₄alkyl,—NHR¹⁰, cyano, —CF3, Ci_₄alkyloxy, C3-₆cycloalkyl, -0-C3-6cycloalkyl,C₂-₆alkenyl, Ci_₄alkyl, and Ci_₄alkyl substituted with one Ci_₄alkyloxy;andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci_₄alkyl;C3-₆cycloalkyl; Ci_₄alkyl substituted with one, two or three halo atoms;and C3-₆cycloalkyl substituted with one, two or three halo atoms;R¹⁰ represents —(C=0)-Ci_₄alkyl; C3-₆cycloalkyl; R¹³; R¹⁴;C3-₆cycloalkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and—O-Ci_₄alkyl; Ci_₄alkyl substituted with one, two or three substituentseach independently selected from the group consisting of halo, —OH and-0-Ci_₄alkyl; or Ci_₄alkyl substituted with one substituent selectedfrom the group consisting of C3-6cycloalkyl, R¹³ and R¹⁴;R¹³ represents a 4- to 7-membered monocyclic aromatic ring containingone, two or three heteroatoms each independently selected from O, S,S(=0)_(p) and N; said 4- to 7-membered monocyclic aromatic ring isoptionally substituted with one or two substituents selected from thegroup consisting of Ci_₄alkyl;p represents 1 or 2;R¹⁴ represents phenyl optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo;Het represents a bicyclic aromatic heterocyclic ring system selectedfrom the group consisting of (a-1), (a-2) and (a-3);R^(3a), R³ ^(d) and R^(3e) each independently represent hydrogen, halo,—NR⁷ ^(a) R^(7b), Ci_₄alkyl, C₂-₄alkenyl, C3-₆cycloalkyl, —OH, or-0-Ci_₄alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, C3-₆cycloalkyl, or Ci_₄alkyl;R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) each independently representhydrogen, halo, —NR⁸ ^(a) R^(8b), or Ci_₄alkyl;R⁸ ^(a) and R^(8b) each independently represent hydrogen or Ci-₄alkyl;Q¹ represents N or CR⁶ ^(a) ;Q² represents N or CR^(6b);Q⁸ represents N or CR^(6g);Q⁹ represents N or CR^(6h);Q¹⁰ represents N or CR^(6i);Q¹¹ represents N or CR^(6j);Q⁵ represents CR³ ^(d) ; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents CR³ ^(d) ; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents CR^(4f); orQ⁵ represents N; Q⁶ represents N; and Q⁷ represents N;R⁶ ^(a) , R^(6b), R^(6g), R^(6h), R^(6i) and R^(6j) each independentlyrepresent hydrogen, halogen, Ci_₄alkyl, —NR⁹ ^(a) R^(9b), or Ci-4alkylsubstituted with one, two or three halo atoms;R⁹ ^(a) and R^(9b) each independently represent hydrogen or Ci-₄alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I).

whereinR¹ represents hydrogen or —C(═O)—C₁₋₄alkyl;R² represents hydrogen or —C(═O)—C₁₋₄alkyl;Y represents —CH₂— or —CF₂—;Z represents —CH₂—, —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, —CR^(5a)R^(5b)—X—, or —C≡C—;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), Rye, R^(5f), R^(5g), and R⁵ ^(h) eachindependently represent hydrogen or Ci_₄alkyl;X represents -0-, —S—, or —NR¹¹—;R¹¹ represents hydrogen, Ci_₄alkyl, or Ci_₄alkyl substituted with onesubstituent selected from the group consisting of —OH, -0-Ci_₄alkyl,—NH₂, —NH-Ci_₄alkyl, and —N(Ci_₄alkyl)₂;Ar represents a monocyclic aromatic ring selected from pyridinyl andimidazolyl; or a 9-membered bicyclic aromatic ring system consisting ofa 6-membered ring fused with a 5-membered ring, containing one, two orthree heteroatoms each independently selected from O, S, and N,said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —OH, —NH₂, —NH-Ci_₄alkyl,—NHR¹⁰, cyano, —CF₃, Ci-₄alkyloxy, C₃-₆cycloalkyl, -0-C₃_6 cycloalkyl,C₂-₆-alkenyl, Ci_₄alkyl, and Ci_₄alkyl substituted with oneCi_₄alkyloxy; andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci_₄alkyl;C₃-₆cycloalkyl; Ci_₄alkyl substituted with one, two or three halo atoms;and C3-₆cycloalkyl substituted with one, two or three halo atoms;R¹⁰ represents —(C=0)-Ci-4alkyl; C₃-₆cycloalkyl; R¹³; R¹⁴;C3-₆cycloalkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and-0-Ci-4alkyl; Ci-4alkyl substituted with one, two or three substituentseach independently selected from the group consisting of halo, —OH and-0-Ci_4 alkyl; or Ci-4alkyl substituted with one substituent selectedfrom the group consisting of C3-6cycloalkyl, R¹³ and R¹⁴;R¹³ represents a 4- to 7-membered monocyclic aromatic ring containingone, two or three heteroatoms each independently selected from O, S,S(=0)_(p) and N; said 4- to 7-membered monocyclic aromatic ring isoptionally substituted with one or two substituents selected from thegroup consisting of Ci-4alkyl;p represents 1 or 2;R¹⁴ represents phenyl optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo;Het represents (a-1);R³ ^(a) represents hydrogen, halo, —NR⁷ ^(a) R^(7b), Ci-4alkyl, C₂_4alkenyl, C3-₆cycloalkyl, —OH, or -0-Ci_₄alkyl;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen, C3-₆cycloalkyl, or Ci-4alkyl;R^(4a) represents hydrogen, halo, —NR⁸ ^(a) R^(8b), or Ci-4alkyl;R⁸ ^(a) and R^(8b) each independently represent hydrogen or Ci-4alkyl;Q¹ represents N or CR⁶ ^(a) ;Q² represents N or CR^(6b);R⁶ ^(a) and R^(6b) each independently represent hydrogen, halogen,Ci-4alkyl, —NR⁹ ^(a) R^(9b), or Ci_4 alkyl substituted with one, two orthree halo atoms;R⁹ ^(a) and R^(9b) each independently represent hydrogen or Ci-4alkyl;and pharmaceutically acceptable addition salts, and solvates thereof.

Another embodiment of the present invention relates to those compoundsof Formula (I), and pharmaceutically acceptable addition salts, andsolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein one or more of the following restrictionsapply:

(i) R¹ and R² represent hydrogen;(ii) Y represents —CH₂;(iii) Z represents —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—, or—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —;(iv) R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), and R⁵^(h) represent hydrogen;(v) X represents -0-;(vi) Ar represents a monocyclic aromatic ring selected from pyridinyland imidazolyl; or a 9-membered bicyclic aromatic ring system consistingof a 6-membered ring fused with a 5-membered ring, containing one, twoor three heteroatoms each independently selected from O, S, and N,said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —NH₂, —NH-Ci_4 alkyl, —CF₃, C₃-₆cycloalkyl, andCi-4alkyl; andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci-4alkyl;(vii) Het represents (a-1);(viii) R³ ^(a) represents halo, —NR⁷ ^(a) R^(7b), or -0-Ci_₄alkyl;(ix) R⁷ ^(a) represents hydrogen; R^(7b) represents hydrogen, orCi-₄alkyl;(x) R^(4a) represents hydrogen;(xi) Q¹ represents CR⁶ ^(a) ; Q² represents CR^(6b);(xii) R⁶ ^(a) and R^(6b) represent hydrogen, or halogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

R¹ and R² represent hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

R¹ represents —C(=0)-C₁₋₄alkyl; R² represents —C(=0)-C₁₋₄alkyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Y represents —CH₂—.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein maximum one of Q¹ and Q² represents N.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Q¹ represents CR^(6A); and Q² r_(e)pr_(e se)nt_(s)CR^(6b); in particular wherein Q¹ represents CH; and Q² represents CH.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het represents (a-1)

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het represents (a-1); Q¹ represents CR^(6A); and Q²represents CR^(6b); in particular wherein Q¹ represents CH; and Q2represents CH.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Q⁵ represents CR^(3d); Q⁶ represents N; and Q⁷ represents CR^(4F); orQ⁵ represents CR^(3D); Q⁶ represents CR^(4E); and Q⁷ represents N; orQ⁵ represents N; Q⁶ represents CR^(4E); and Q⁷ represents CR^(4F); orQ⁵ represents N; Q⁶ represents CR^(4e); and Q⁷ represents N.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het represents a bicyclic aromatic heterocyclicring system selected from the group consisting of (a-1) and (a-2).

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Het represents a bicyclic aromatic heterocyclicring system of Formula (a-1)

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Het represents a bicyclic aromatic heterocyclic ring system of Formula(a-1);R¹ and R² represent hydrogen; andR¹⁰ represents —(C=0)-Ci-4alkyl; C3-₆cycloalkyl; C3-₆cycloalkylsubstituted with one, two or three substituents each independentlyselected from the group consisting of halo, —OH and -0-Ci-4alkyl;Ci-4alkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and-0-Ci-4alkyl; or Ci_4alkyl substituted with one C3-6cycloalkyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

R¹⁰ represents —(C=0)-Ci_4alkyl; C3-₆cycloalkyl; C3-₆cycloalkylsubstituted with one, two or three substituents each independentlyselected from the group consisting of halo, —OH and -0-Ci-4alkyl;Ci-4alkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and-0-Ci-4alkyl; or Ci_4alkyl substituted with one C3-6cycloalkyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

R^(3a), R^(3d), R^(3e) represent hydrogen, halo, —NR⁷ ^(a) R⁷ ^(b) , or—O—CV₄alkyl; in particular R³ ^(a) , R³ ^(d) , R^(3e) r_(e)pr_(esent)halo, —NR^(7a)R^(7b), or —O—CVialkyl;R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g) represent hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a monocyclic aromatic ring as definedin any other embodiments, or Ar represents a bicyclic ring systemaccording to definition (i) or (ii).

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a monocyclic aromatic ring selectedfrom pyridinyl and imidazolyl; or a 9-membered bicyclic aromatic ringsystem selected from the group consisting of

said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Ar represents a monocyclic aromatic ring selected from 2-pyridinyl,3-pyridinyl, 4-pyridinyl, 1H-imidazol-4-yl and 1H-imidazol-5-yl; or a9-membered bicyclic aromatic ring system selected from the groupconsisting of

wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Ar represents a monocyclic aromatic ring selected from 2-pyridinyl,3-pyridinyl, 4-pyridinyl, 1H-imidazol-4-yl and 1H-imidazol-5-yl; or a9-membered bicyclic aromatic ring system selected from the groupconsisting of

wherein Ar is substituted in the position indicated by a (if any) with—NH₂, —NH—CV ₄alkyl, or —NHR¹⁰; and wherein Ar is optionally substitutedwith substituents selected from the list of substituents on Ar in any ofthe other embodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a monocyclic aromatic ring selectedfrom pyridinyl and imidazolyl; in particular 2-pyridinyl, 3-pyridinyl,4-pyridinyl, 1H-imidazol-4-yl or 1H-imidazol-5-yl; wherein Ar isoptionally substituted according to any of the embodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a monocyclic aromatic ring selectedfrom the group consisting of pyridinyl, pyrimidinyl, pyrazolyl, andimidazolyl;

wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Ar represents a bicyclic ring system;wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a 9-membered bicyclic aromatic ringsystem consisting of a 6-membered ring fused with a 5-membered ring,containing one, two or three heteroatoms each independently selectedfrom O, S, and N,

said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a 10-membered bicyclic aromatic ringsystem consisting of two fused 6-membered rings, wherein optionally 1 or2 ring carbon atoms are replaced by a nitrogen atom; provided that whenthe nitrogen atom replaces one of the two fused carbon atoms, a carbonylgroup is present in said bicyclic aromatic ring system; provided that incase Ar represents a 10-membered bicyclic aromatic ring system, Z canonly represent —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)— or—CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —;

wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a 9-membered bicyclic aromatic ringsystem consisting of a 6-membered ring fused with a 5-membered ring,containing one, two or three heteroatoms each independently selectedfrom O, S, and N,

said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring; orwherein Ar represents a 10-membered bicyclic aromatic ring systemconsisting of two fused 6-membered rings, wherein optionally 1 or 2 ringcarbon atoms are replaced by a nitrogen atom; provided that when thenitrogen atom replaces one of the two fused carbon atoms, a carbonylgroup is present in said bicyclic aromatic ring system; provided that incase Ar represents a 10-membered bicyclic aromatic ring system, Z canonly represent —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) — or—CR^(5a)R⁵ ^(b) —CR^(5c)R^(5d)—CR⁵ ^(e) R^(5g)—CR^(5i)R⁵ ^(h) —;wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents

a fused bicyclic partially aromatic ring system which is attached withthe aromatic ring to linker Z, wherein the fused bicyclic partiallyaromatic ring system is selected from (b-1), (b-2) and (b-3),wherein ring A is a monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl and imidazolyl;wherein ring B is a C₅_ecycloalkyl or a 5- to 6-membered saturatedheterocyclyl containing one or two heteroatoms each independentlyselected from O, S and N;wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a 9-membered bicyclic aromatic ringsystem selected from

wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a 10-membered bicyclic aromatic ringsystem selected from

wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a fused bicyclic partially aromaticring system selected from

wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a monocyclic aromatic ring selectedfrom pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl; or a bicyclicring system selected from

wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a 9-membered bicyclic aromatic ringsystem selected from the group consisting of

said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a 9-membered bicyclic aromatic ringsystem selected from the group consisting of

wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a 9-membered bicyclic aromatic ringsystem selected from the group consisting of

wherein Ar is substituted in the position indicated by a (if any) with—NH₂, —NH-G-₄alkyl, or —NHR¹⁰; and wherein Ar is optionally substitutedwith substituents selected from the list of substituents on Ar in any ofthe other embodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar represents a bicyclic ring system selected fromthe group consisting of

wherein Ar is substituted in the position indicated by a (if any) with—NH₂, —NH-Ci_₄alkyl, or —NHR¹⁰;wherein Ar is substituted in the position indicated by β (if any) withoxo;wherein Ar is substituted in the position indicated by γ (if any) withCi-₄alkyl;and wherein Ar is optionally substituted with substituents selected fromthe list of substituents on Ar in any of the other embodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, or —CR^(5a)R⁵^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —;R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), and R⁵^(i) represent hydrogen;Ar represents a bicyclic ring system selected from the group consistingof

wherein Ar is substituted in the position indicated by a (if any) with—NH₂.

In an embodiment, the present invention relates to those compounds ofFormula (I′) and pharmaceutically acceptable addition salts, andsolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

Z represents —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, or—CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)—; R^(5a),R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), and R⁵ ^(i)represent hydrogen;Ar represents a bicyclic ring system selected from the group consistingof

wherein Ar is substituted in the position indicated by a with —NH₂.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Ar is substituted with one substituent selectedfrom the group consisting of —NH₂, —NH—C₁₋₄alkyl, —NHR¹⁰; and wherein Aris optionally substituted with another substituent selected from thelist of substituents on Ar in any of the other embodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Ar represents a monocyclic aromatic ring selected from pyridinyl andimidazolyl;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —OH, —NH₂, —NH—C₁₋₄alkyl, —NHR¹⁰, cyano, —CF₃,Ci-4alkyloxy, C₃-ecycloalkyl, -0-C₃-ecycloalkyl, C₂_6alkenyl, Ci-4alkyl,and Ci-4alkyl substituted with one Ci-4alkyloxy.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Ar represents a monocyclic aromatic ring selected from pyridinyl andimidazolyl;wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Ar represents a 9-membered bicyclic aromatic ring system consisting of a6-membered ring fused with a 5-membered ring, containing one, two orthree heteroatoms each independently selected from O, S, and N,said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;Ar is optionally substituted on the carbon atoms with in total one, two,three or four substituents each independently selected from the groupconsisting of halo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃,Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃-₆cycloalkyl, C₂_6alkenyl, Ci-4alkyl,and Ci-4alkyl substituted with one Ci-4alkyloxy; andwhere possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci-4alkyl;C₃-₆cycloalkyl; Ci-4alkyl substituted with one, two or three halo atoms;and C₃-₆cycloalkyl substituted with one, two or three halo atoms.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Ar represents a 9-membered bicyclic aromatic ring system consisting of a6-membered ring fused with a 5-membered ring, containing one, two orthree heteroatoms each independently selected from O, S, and N,said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring;wherein Ar is optionally substituted according to any of theembodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein R⁵ ^(b, R) ⁵ g and R^(5h) represent hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Q¹ represents CR⁶ ^(a) ; and Q² represents CR^(6b).

In an embodiment, the present invention relates to those compounds ofFormula (I′) and pharmaceutically acceptable addition salts, andsolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein

R^(5b), R^(5g) and R⁵ ^(h) represent hydrogen;Y represents —CH₂—;Het represents (a-1);Q^(I) r_(e)pre_(se)nts CR^(6a); and Q² represents CR⁶ ^(b) ; inparticular wherein Q represents CH; and Q² represents CH.

In an embodiment, the present invention relates to those compounds ofFormula (I′) and pharmaceutically acceptable addition salts, andsolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein Q² represents CR⁶ ^(b) .

In an embodiment, the present invention relates to those compounds ofFormula (I′) and pharmaceutically acceptable addition salts, andsolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein Y represents —CH₂—.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—, or—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —;R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), and R⁵ ^(h)represent hydrogen;X represents -0-.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—, or—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Z represents —CH₂—, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —, or —C≡C—.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Z represents —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —, —CR⁵ ^(a) R⁵ ^(b)—X—, or —C≡C—.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —X—CR^(5a)R^(5b).

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Z represents —O-CH2-.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —X—CR⁵ ^(a) R⁵ ^(b) —; X represents -0-; and R⁵ ^(a) andR^(5b) represent hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

X represents —O— or —NR¹¹—; in particular X represents -0-.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

R⁷ ^(a) and R⁷ ^(b) represent hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Met represents (a-1); R_(3a) repre_(s)ent_(s)—NR⁷^(a) R^(7b); and R^(7a) and R^(7b) represent hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein R³ ^(a) , R³ ^(d) and R³ ^(e) represent other thanhalo.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

R³ ^(a) , R³ ^(d) and R^(3e) represent —NR⁷ ^(a) R⁷ ^(b) ;R^(7a) represents hydrogen;R^(7b) represents hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein R³ ^(a) , R³ ^(d) and R^(3e) represent —NH₂.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —,—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, or —CR⁵ ^(a) R⁵ ^(b)—CR^(5e)R^(5d)—CR^(5e)R^(5g)—CR⁵ ^(i) R⁵ ^(h) —;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), and R⁵^(i) each independently represent hydrogen or Ci-₄alkyl;X represents -0-;Het represents a bicyclic aromatic heterocyclic ring system (a-1);R³ ^(a) represents halo, —NR⁷ ^(a) R^(7b), or —O-Ci_₄alkyl;Q¹ represents CR⁶ ^(a) ;Q² represents CR^(6b).

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵^(h) —, or —CR^(5a)R⁵ ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h)—;R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), and R^(5h)each independently represent hydrogen or Ci_₄alkyl;X represents -0-;Het represents a bicyclic aromatic heterocyclic ring system (a-1);R³ ^(a) represents —NR⁷ ^(a) R^(7b);R⁷ ^(a) and R^(7b) represent hydrogen;Q¹ represents CR⁶ ^(a) ;Q² represents CR^(6b).

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —CH₂—, —CHR⁵ ^(i) —, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5i)R^(5h)—,—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, or—CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)—;R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), and R⁵^(i) each independently represent hydrogen or Ci_₄alkyl;Het represents a bicyclic aromatic heterocyclic ring system (a-1);R³ ^(a) represents halo, —NR⁷ ^(a) R^(7b), or -0-Ci_₄alkyl;Q¹ represents CR⁶ ^(a) ;Q² represents CR^(6b).

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R^(5h)—,—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)—, or—CR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R^(5h)—;R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), and R^(5h) eachindependently represent hydrogen or Ci_₄alkyl;Het represents a bicyclic aromatic heterocyclic ring system (a-1);R³ ^(a) represents —NR⁷ ^(a) R^(7b);R^(7a) and R^(7b) represent hydrogen;Q¹ represents CR⁶ ^(a) ;Q² represents CR^(6b).

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein the compounds of Formula (I) are restricted tocompounds of Formula (I-a1):

It will be clear that all variables in the structure of Formula (I-al),may be defined as defined for the compounds of Formula (I) or anysubgroup thereof as mentioned in any of the other embodiments.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein the compounds of Formula (I) are restricted tocompounds of Formula (I-al):

wherein R^(3a) represents —NH₂; and R^(4a) represents hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Z represents —X—CR^(5a)R^(5b)— or —CH2CH2-.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —X—CR^(5a)R^(5b)— or —CH2CH2-;R^(5b) represents hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

R^(5b) represents hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —X—CR^(5a)R^(5b)— or —CH2CH2-;R^(5a) and R^(5b) represent hydrogen;X represents -0-.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —X—CR^(5a)R^(5b)— or —CH2CH2-;R^(5a) and R^(5b) represent hydrogen;X represents -0-;Het represents (a-1).

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Z represents —X—CR^(5a)R^(5b)— or —CH2CH2-;R^(5a) and R^(5b) represent hydrogen;X represents -0-;Het represents (a-1);_(R) 3a r_(e)pr_(e S)ents —NR^(7a)R^(7b);R^(7a) represents hydrogen;R^(7b) represents hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein X represents -0-.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

Het represents (a-1);7a_(R) 3a r_(e)pr_(esents)—NR^(7a)R^(7b);R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

R^(3a), R^(3d) and R^(3e) represent —NR⁷ ^(a) R⁷ ^(b) ;R^(7a) represents hydrogen;R⁷ ^(b) represents hydrogen, C3-6cycloalkyl, or Ci-₄alkyl.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

R³ ^(a) , R³ ^(d) and R³ ^(e) represent —NR⁷ ^(a) R⁷ ^(b) ;R⁷ ^(a) represents hydrogen;R^(7b) represents hydrogen.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein Y represents —CH₂—; and Z represents —CH2CH2-.

In an embodiment, the present invention relates to those compounds ofFormula (I) and pharmaceutically acceptable addition salts, and solvatesthereof, or any subgroup thereof as mentioned in any of the otherembodiments, wherein

R¹ represents hydrogen; R² represents hydrogen;Y represents —CH₂—;Z represents —CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —,—CR^(5c)═CR^(5d)—, —CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —,—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —, or —CR^(5a)R⁵ ^(b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) —;R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), and R⁵^(i) each independently represent hydrogen or Ci-₄alkyl;X represents -0-;Het represents a bicyclic aromatic heterocyclic ring system (a-1);R³ ^(a) represents halo, —NR⁷ ^(a) R^(7b), or -0-Ci_₄alkyl;R^(7a) represents hydrogen;R^(7b) represents hydrogen or Ci_₄alkyl;R^(4a) represents hydrogen;Q¹ represents CR⁶ ^(a) ;Q² represents N or CR^(6b);R⁶ ^(a) and R^(6b) each independently represent hydrogen or halogen.

In an embodiment, the present invention relates to a subgroup of Formula(I) as defined in the general reaction schemes.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of any of the exemplified compounds,

and the free bases, the pharmaceutically acceptable addition salts, andthe solvates thereof.

All possible combinations of the above-indicated embodiments areconsidered to be embraced within the scope of this invention.

Methods for the Preparation

In this section, as in all other sections unless the context indicatesotherwise, references to Formula (I) also include all other sub-groupsand examples thereof as defined herein.

The general preparation of some typical examples of the compounds ofFormula (I) is described hereunder and in the specific examples, and aregenerally prepared from starting materials which are either commerciallyavailable or prepared by standard synthetic processes commonly used bythose skilled in the art. The following schemes are only meant torepresent examples of the invention and are in no way meant to be alimit of the invention.

Alternatively, compounds of the present invention may also be preparedby analogous reaction protocols as described in the general schemesbelow, combined with standard synthetic processes commonly used by thoseskilled in the art of organic chemistry.

The skilled person will realize that in the reactions described in theSchemes, it may be necessary to protect reactive functional groups, forexample hydroxy, amino, or carboxy groups, where these are desired inthe final product, to avoid their unwanted participation in thereactions. Conventional protecting groups can be used in accordance withstandard practice. This is illustrated in the specific examples.

The skilled person will realize that in the reactions described in theSchemes, it may be advisable or necessary to perform the reaction underan inert atmosphere, such as for example under N₂-gas atmosphere, forexample when NaH is used in the reaction.

It will be apparent for the skilled person that it may be necessary tocool the reaction mixture before reaction work-up (refers to the seriesof manipulations required to isolate and purify the product(s) of achemical reaction such as for example quenching, column chromatography,extraction).

The skilled person will realize that heating the reaction mixture understiffing may enhance the reaction outcome. In some reactions microwaveheating may be used instead of conventional heating to shorten theoverall reaction time.

The skilled person will realize that another sequence of the chemicalreactions shown in the Schemes below, may also result in the desiredcompound of Formula (I).

The skilled person will realize that intermediates and compounds shownin the schemes below may be further functionalized according to methodswell-known by the person skilled in the art.

The skilled person will realize that more Compounds of Formula (I) canbe prepared by using similar synthetic protocols as described in theSchemes below.

In case one of the starting materials is available as a salt form, theskilled person will realize that it may be necessary to first treat thesalt with a base, such as for example N,N-diisopropylethyiamine (DIPEA).

All variables are defined as mentioned hereabove unless otherwise isindicated or is clear from the context.

The skilled person will understand that analogous chemistry as describedin Schemes 1 to 9 (wherein Met is showns as (a-1)), may also be appliedto make compounds of Formula (I) wherein Het represents a bicyclicaromatic heterocyclic rings system (a-2) or (a-3). In addition, thisinformation may be combined with standard synthetic processes commonlyused by those skilled in the art of organic chemistry to obtain morecompounds of Formula (I) wherein Het represents (a-2) or (a-3).

In general, compounds of Formula (I) can be prepared according to Scheme1:

In scheme 1, ‘LGi’ is defined as a suitable leaving group such as forexample halogen. All other variables in Scheme 1 are defined accordingto the scope of the present invention.

In scheme 1, the following reaction conditions typically apply:

1: Different sets of reaction conditions dependent on the definition ofR³ ^(a) :1a: When R³ ^(a) is halogen, step 1 can be skipped.1b: When R³ ^(a) is NR⁷ ^(a) R⁷ ^(b) , in the presence of a suitableamine of formula HNR⁷ ^(a) R^(7b), with a suitable solvent such as forexample, H₂0, MeOH, or EtOH, at a suitable temperature such as forexample between 100-130° C. typical 1 under microwave conditions orusing an autoclave vessel for heating.1c: When R³ ^(a) is —O-C₁_4 alkyl, in the presence of a suitableHO-Ci-4alkyl, with a suitable base such as for example NaH, potassiumtert-butoxide (tBuOK) in a suitable solvent such as for exampletetrahydrofuran (THF) at a suitable temperature. Alternatively in thepresence of the suitable HO-G-ialkyl as solvent with a suitable acidsuch as for example HCl.1d: When R³ ^(a) is hydrogen, under hydrogenation conditions: H₂-gasatmosphere in the presence of a catalyst such as for example Raney Ni,Pd/C (for example 5 vvt % or 10 vvt %) or Pt/C (for example 5 wt %) in asuitable solvent such as for example methanol (MeOH), ethanol (EtOH) orTHF.1e: When R³ ^(a) is CV-ialkyl, in the presence of a suitable boron isacid or ester such as for example methylboronic acid with a suitablecatalyst such as for example 1,1′-bis(diphenyl phosphino)ferrocene andwith with a suitable base such as for example K3PO4 in a in a suitablesolvent mixture such as for example dioxane/H₂0 ratio 5 to 1 at asuitable temperature such as for example 100° C.2: in the presence of a suitable acid, such as for example 4M HCl indioxane or 4M HCl in MeOH, with a suitable solvent such as for exampleMeOH at a suitable temperature such as for example room temperature; oralternatively in the presence of a suitable acid such as for exampletrifluoroacetic acid (TEA) in dichloromethane (DCM) at a suitabletemperature, or acetic acid in THF and water at a suitable temperaturesuch as for example room temperature.3: in the presence of suitable acid anhydride of formula(C₁₋₄alkylC=O)₂O with a suitable solvent such as pyridine at a suitabletemperature. When R³ ^(a) is NH₂, (Ci_₄alkylC=O)₂O can react with theNH₂ to obtain the N(C₁₋₄alkylC=O)₂ intermediate. Such an intermediatecan be converted to the targeted product in a suitable solvent such asfor example MeOH at a suitable temperature such as for example 100-130°C. under microwave conditions or using an autoclave vessel for heating.The reaction may benefit from the presence of an acid, such as HCl orC₁₋₄ alkylC0₂H.

The starting materials in scheme 1 are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in following general schemes.

General Scheme 2a

In general, intermediates of Formula III wherein Z represents -0-CHR⁵^(a) — can be prepared according to Scheme 2a. All other variables inScheme 2a are defined according to the scope of the present invention.The skilled person will realize a suitable protection group is neededwhen R³ ^(a) is —NH₂ or —NHR⁷ ^(b) ;

In scheme 2a, the following reaction conditions apply:

1: The Mitsunobu reaction:

-   -   1a: In the presence of PPln-Polymer supported, diisopropyl        azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) or        Bis(1,1-dimethylethyl)-azodicarboxylate (DBAD) in a suitable        solvent such as for example anhydrous THF at a suitable        temperature such as for example room temperature.    -   1b: In the presence of triphenylphosphine (PPh₃), DIAD or DEAD        in a suitable solvent such as for example anhydrous THF at a        suitable temperature such as for example room temperature.    -   1c: In the presence of cyanomethylenetributylphosphorane (CMBP)        or cyanomethylenetrimethylphosphorane (CMMP), in a suitable        solvent such as for example anhydrous toluene at a suitable        temperature such as for example 80° C.

The starting materials in scheme 2a are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in following general schemes. The skilled person will realizethat when R^(5a) is CV₄alkyl, the different isomers can be separatedfrom each other by using Reversed-Phase High-Performance LiquidChromatography (RP-HPLC) or Supercritical Fluid Chromatography (SFC).

General Scheme 2b

In general, intermediates of Formula III wherein Z represents —CHR^(5a)—can be prepared according to Scheme 2b. All other variables in Scheme 2bare defined according to the scope of the present invention. The skilledperson will realize a suitable protection group is needed when R³ ^(a)is —NH₂ or —NHR^(7b);

In scheme 2b, the following reaction conditions apply:

1: The Mitsunobu reaction:

-   -   1a: In the presence of PPh₃-Polymer supported, diisopropyl        azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) or        Bis(1, 1-dimethylethyl)-azodicarboxylate (DBAD) in a suitable        solvent such as for example anhydrous THF at a suitable        temperature such as for example room temperature.    -   1b: In the presence of triphenylphosphinc (PPh;), DIAD or DEAD        in a suitable solvent such as for example anhydrous THF at a        suitable temperature such as for example room temperature.    -   1c: In the presence of cyanomethylenetributylphosphorane (CMBP)        or cyanomethylenetrimethylphosphorane (CMMP), in a suitable        solvent such as for example anhydrous toluene at a suitable        temperature such as for example 80° C.

The starting materials in scheme 2b are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in following general schemes. The skilled person will realizethat when R^(5a) is G-4alkyl, the different isomers can be separatedfrom each other by using Reversed-Phase High-Performance LiquidChromatography (RP-HPLC) or Supercritical Fluid Chromatography (SFC).

A skilled person will realize that scheme 2b can also be used toprepared analogous intermediates wherein Z represents —CR^(5e)R^(5g)—CR⁵^(f) R⁵ ^(h) —.

General scheme 2c

Intermediates of Formula 11 wherein Z represents —X^(a)—CHR^(5a)— can beprepared according to Scheme 2c. In scheme 2c, ‘X^(a)’ is defined as Oor S; ‘LG’ is defined as a leaving group such as for example halogen,mesylate (MsO) and tosylate (TosO), preferably TosO. ‘LG₁’ is defined asleaving group such as for example halogen. All other variables in Scheme2c are defined according to the scope of the present invention.

In scheme 2c, the following reaction conditions apply:

1: in the presence of a base such as for example K2CO3, trietylamine(Et₃N) or DIPEA, in a suitable solvent such as CH3CN, DCM orN,N-dimethylacetamide (DMA).

The starting materials in scheme 2c are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in following general schemes. The skilled person will realizethat when R^(5a) is G-4alkyl, the different isomers can be separatedfrom each other by using Reversed-Phase High-Performance LiquidChromatography (RP-HPLC) or Supercritical Fluid Chromatography (SFC).

General Scheme 2d

Intermediates of Formula I11 wherein Z represents —X^(a)—CHR^(5a)— canbe prepared according to Scheme 2d. In scheme 2d ‘X^(a)’ is defined as Oor S. ‘LG’ is defined as a leaving group such as for example halogen,MsO or TosO, preferably TosO. All other variables in Scheme 2d aredefined according to the scope of the present invention. The skilledperson will realize that a suitable protection group is needed when R³^(a) is —NH2 or -NHR⁷ ^(b)

In scheme 2d, the following reaction conditions apply:

1: in the presence of a base such as for example K2CO3, Et₃N or DIPEA,in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA).

The starting materials in scheme 2d are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in following general schemes. The skilled person will realizethat when R^(5a) is G-₄alkyl. the different isomers can be separatedfrom each other by using Reversed-Phase High-Performance LiquidChromatography (RP-HPLC) or Supercritical Fluid Chromatography (SFC).

General Scheme 3

In general, intermediates wherein Z represents —X-CHR⁵ ^(a) —; andwherein X represents —NH— or —NR¹¹— can be prepared according to Scheme3. In scheme 3, ‘LG1’ is defined as a leaving group such as for examplehalogen. All other variables in Scheme 3 are defined according to thescope of the present invention.

In scheme 3, the following reaction conditions apply:

1: in the presence of a suitable reduction reagent such as for examplesodium triacetoxyborohydride (NaBH(AcO)₃) together with a suitablesolvent such as for example DCM at a suitable temperature such as forexample room temperature; or alternatively NaBH ₃CN together with asuitable solvent such as for example MeOH at a suitable temperature suchas for example between room temperature and 50° C.2: in the presence of a suitable base such as for example NaH togetherwith a suitable solvent such as for example anhydrous THF,N,N-dimethylformamide (DMF), DMA at a suitable temperature such as forexample between room temperature and 50° C.

The starting materials in scheme 3 are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in the specific experimental part. The skilled person willrealize that when R^(5a) is Ci-4alkyl, the different isomers can beseparated from each other by using Reversed-Phase High-PerformanceLiquid Chromatography (RP-HPLC) or Supercritical Fluid Chromatography(SFC).

General Scheme 4

In general, intermediates wherein Z represents —C≡C—, —CH═CH—, or—CH2-CH2- can be prepared according to Scheme 4. In scheme 4, ‘LGi’ isdefined as a leaving group such as for example halogen. All othervariables in Scheme 4 are defined according to the scope of the presentinvention.

In scheme 4, the following reaction conditions apply:

1: In the presence of suitable amine, such as HNR′R″ or NaOR′, with asuitable solvent such as for example H₂0, MeOH, or EtOH at a suitabletemperature such as for example between 100-130° C. under microwavecondition or using an autoclave vessel for heating.2: In the presence of a suitable Ar-bromide or Ar-iodide, a suitablecatalyst, such as bis(triphenylphosphine)palladium(ll) dichloride andcopper(l) iodide in a suitable solvent, such as 2-methyltetrahydrofuranwith a suitable base, such as for example triethylamine at a suitabletemperature, such as for example 80° C.3: in the presence of a suitable Ar-bromide or Ar-iodide, a suitablesalt, such as for example tetraethylammonium chloride (Et₄NCl), in asuitable solvent, such as for example DMF, with a suitable base such asfor example DIPEA and a palladium catalyst, such as for example Pd(OAc):(palladium(I!) acetate) at suitable temperature such as for example 100°C.4: in the presence of a H₂-gas atmosphere and a catalyst such as forexample Pd/C (for example 5 wt % or 10 wt %) in a suitable solvent suchas for example MeOH.

The starting materials in scheme 4 are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in the specific experimental part.

General Scheme 5

In general, intermediates wherein Z represents —CH2O— can be preparedaccording to Scheme 5. In scheme 5, ‘LG₁’ is defined as a leaving groupsuch as for example halogen. All other variables in Scheme 5 are definedaccording to the scope of the present invention.

In scheme 5, the following reaction conditions apply:

1: in the presence of a base such as for example K2CO3, Et₃N or DIPEA,in a suitable solvent such as CH3CN, DCM or N,N-dimethylacetamide (DMA).

General Scheme 6

In general, intermediates wherein Z represents —CH2- can be preparedaccording to Scheme 6. In scheme 6, ‘LGi’ is defined as a leaving groupsuch as for example halogen. All other variables in Scheme 6 are definedaccording to the scope of the present invention.

In scheme 6, the following reaction conditions apply:

1: In the presence of tosylhydrazide, with a suitable solvent such asfor example, MeOH, EtOH, or DCM at a suitable temperature such as roomtemperature.2: In the presence of Boronic acids, with a suitable base such as K2CO3,Na₂CO₃, CS2CO3, with a suitable solvent such as for example, 1,4-dioxaneat a suitable temperature such 90° C.

The starting materials in scheme 6 are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in the specific experimental part.

General Scheme 7

In general, intermediates wherein Z represents —CH2-CH2- can be preparedaccording to Scheme 7. In scheme 7, ‘LGi’ is defined as a leaving groupsuch as for example halogen. All other variables in Scheme 7 are definedaccording to the scope of the present invention.

In scheme 7, the following reaction conditions typically apply:

1: In a first step in the presence of an alkene precursor and a9-Borabicycio(3.3.1)nonane (9-BBN) solution 0.5 M in THF under nitrogenatmosphere at a temperature between room temperature and reflux and areaction time between 1 to 3 hours. In a second step in the presence of,for example, a suitable Ar-bromide or Ar-iodide and a suitable catalystas for example1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and in thepresence of a suitable base as for example potassium phosphate tribasicin a suitable solvent mixture as for example THF and water at a suitabletemperature between 50° C. and reflux and a suitable reaction timebetween 1 and 3 hours.2: Different sets of reaction conditions dependent on the definition ofR^(3a):2a: When R^(3a) is halogen, step 1 can be skipped;2b: When R^(3a) is NR^(7a)R^(7b), in the presence of a suitable amine offormula HNR^(7a)R^(7b), with a suitable solvent such as for example,H2O, MeOH, or EtOH, at a suitable temperature such as for examplebetween 100-130° C. typical under microwave conditions or using anautoclave vessel for heating.2c: When R^(3a) is —O-G-ialkyl, in the presence of a suitableHO-G-talkyl, with a suitable base such as for example Nail, potassiumtert-butoxide (tBuOK) in a suitable solvent such as for exampletetrahydrofuran (THF) at a suitable temperature. Alternatively in thepresence of the suitable HO—C₁₋₄alkyl as solvent with a suitable acidsuch as for example HCl.2d: When R^(3a) is hydrogen, under hydrogenation conditions: lb-gasatmosphere in the presence of a catalyst such as for example Raney Ni,Pd/C (for example 5 wt % or 10 wt %) or Pt/C (for example 5 wt %) in asuitable solvent such as for example methanol (MeOH), ethanol (EtOH) orTHF:2e: When R³ ^(a) is G alkyl, in the presence of a suitable boronic acidor ester such as for example methylboronic acid with a suitable catalystsuch as for example 1, Γ-bisidiphenylphosphino (ferrocene and with witha suitable base such as for example K3PO4 in a in a suitable solventmixture such as for example dioxane/H₂0 ratio 5 to 1 at a suitabletemperature such as for example ₁₀₀° C.

The starting materials in scheme 7 are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in the specific experimental part.

General Scheme 8

In general, intermediates wherein Z represents —CH2-CH2- can be preparedaccording to Scheme 8. In scheme 8, ‘LGi’ is defined as a leaving groupsuch as for example halogen. All other variables in Scheme 8 are definedaccording to the scope of the present invention.

In scheme 8, the following reaction conditions typically apply:

1: Different sets of reaction conditions dependent on the definition ofR³ ^(a) :1a: When R³ ^(a) is halogen, step 1 can be skipped.1b: When R³ ^(a) is NR⁷ ^(a) R^(7b), in the presence of a suitable amineof formula HNR⁷ ^(a) R^(7b), with a suitable solvent such as forexample, ¾0, MeOH, or EtOH, at a suitable temperature such as forexample between 100-130° C. typical I under microwave conditions orusing an autoclave vessel for heating.1c: When R³ ^(a) is —O—Ci_₄alkyl, in the presence of a suitableHO-Ci-₄alkyl, with a suitable base such as for example NaH, potassiumtert-butoxide (tBuOK) in a suitable solvent such as for exampletetrahydrofuran (THF) at a suitable temperature. Alternatively in thepresence of the suitable HO-Ci-₄alkyl as solvent with a suitable acidsuch as for example HCl.Id: When R³ ^(a) is hydrogen, under hydrogenation conditions: Eb-gasatmosphere in the presence of a catalyst such as for example Raney Ni,Pd/C (for example 5 wt % or 10 wt %) or Pt/C (for example 5 wt %) in asuitable solvent such as for example methanol (MeOH), ethanol (EtOH) orTHF.1e: When R³ ^(a) is G in the presence of a suitable boronic acid orester such as for example methylboronic acid with a suitable catalystsuch as for example 1, Γ-bis(diphenylphosphino (ferrocene and with witha suitable base such as for example K₃P0₄ in a in a suitable solventmixture such as for example dioxane/H₂0 ratio 5 to 1 at a suitabletemperature such as for example ₁₀₀° C.2: In a first step in the presence of an alkene precursor and a 9-BBNsolution 0.5 M in THF under nitrogen atmosphere at a temperature betweenroom temperature and reflux and a reaction time between 1 to 3 hours. Ina second step in the presence of suitable Ar-bromide or Ar-iodide and asuitable catalyst as for example 1,Γ-bis(diphenylphosphino)ferrocene]dichioropalladium(II) and in thepresence of a suitable base as for example potassium phosphate tribasicin a suitable solvent mixture as for example THF and water at a suitabletemperature between 50° C. and reflux and a suitable reaction timebetween 1 and 3 hours.

The starting materials in scheme 8 are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in the specific experimental part.

General Scheme 9

In general, intermediates as shown in Scheme 9 wherein Z represents—CH2-CH2- can be prepared according to Scheme 9. In scheme 9, “LG₁’ isdefined as a leaving group such as for example halogen. All othervariables in Scheme 9 are defined according to the scope of the presentinvention

1: In a first step in the presence of an alkene precursor and a 9-BBNsolution 0.5 M in THF under nitrogen atmosphere at a temperature betweenroom temperature and reflux and a reaction time between 1 to 3 hours. Ina second step in the presence of, for example, a suitable Ar-bromide orAr-iodide (X being Br or I respectively) and a suitable catalyst as forexample 1,1′-bis(diphenylphosphino)feiTocene]dichloropalladium(II) andin the presence of a suitable base as for example potassium phosphatetribasic in a suitable solvent mixture as for example THF and water at asuitable temperature between 50″C and reflux and a suitable reactiontime between 1 and 3 hours.2: In the presence of triflic anhydride and a suitable base as forexample pyridine in a suitable solvent as for example DCM at a suitabletemperature as for example 0° C. under an inert atmosphere of N₂ gas.3: In the presence of a suitable base as for example CS2CO3 in asuitable solvent as for example DMF at a suitable temperature as forexample room temperature under an inert atmosphere of N ₂ gas.

The starting materials in scheme 9 are commercially available or can beprepared by standard means obvious to those skilled in the art or asdescribed in the specific experimental part.

In all these preparations, the reaction products may be isolated fromthe reaction medium and, if necessary, further purified according tomethodologies generally known in the art such as, for example,extraction, crystallization, trituration and chromatography.

The chi rally pure forms of the compounds of Formula (I) form apreferred group of compounds. It is therefore that the chirally pureforms of the intermediates and their salt forms are particularly usefulin the preparation of chirally pure compounds of Formula (I). Alsoenantiomeric mixtures of the intermediates are useful in the preparationof compounds of Formula (I) with the corresponding configuration.

Pharmacology

It has been found that the compounds of the present invention inhibitPRMT5 activity.

In particular compounds of the present invention bind to the PRMT5enzyme, and competitively with natural substrate SAM(S-adenosyl-L-methionine), to inhibit such enzyme.

It is therefore anticipated that the compounds according to the presentinvention or pharmaceutical compositions thereof may be useful fortreating or preventing, in particular treating, of diseases such as ablood disorder, metabolic disorders, autoimmune disorders, cancer,inflammatory diseases, cardiovascular diseases, neurodegenerativediseases, pancreatitis, multiorgan failure, kidney diseases, plateletaggregation, sperm motility, transplantation rejection, graft rejection,lung injuries and the like.

In particular the compounds according to the present invention orpharmaceutical compositions thereof may be useful for treating orpreventing, in particular treating, of diseases such as allergy, asthma,hematopoietic cancer, lung cancer, prostate cancer, melanoma, metabolicdisorder, diabetes, obesity, blood disorder, sickle cell anemia, and thelike.

The compounds according to the present invention or pharmaceuticalcompositions thereof may be useful for treating or preventing, inparticular treating, of diseases such as a proliferative disorder, suchas an autoimmune disease, cancer, a benign neoplasm, or an inflammatorydisease.

The compounds according to the present invention or pharmaceuticalcompositions thereof may be useful for treating or preventing, inparticular treating, of diseases such as a metabolic disorder comprisingdiabetes, obesity; a proliferative disorder comprising cancer,hematopoietic cancer, lung cancer, prostate cancer, melanoma, orpancreatic cancer; blood disorder; hemoglobinopathy; sickle cell anemia;β-thalassemia, an inflammatory disease, and autoimmune disease e.g.rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome,diarrhea, gastroesophageal reflux disease, and the like.

In some embodiments, the inhibition of PRMT5 by a provided compound maybe useful in treating or preventing, in particular treating, thefollowing non-limiting list of cancers: breast cancer, lung cancer,esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma,medulloblastoma, rectum adenocarcinoma, colon adenocarcinoma, gastriccancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lungadenocarcinoma, head and neck squamous cell carcinoma, brain tumors,hepatocellular carcinoma, renal cell carcinoma, melanoma,oligodendroglioma, ovarian clear cell carcinoma, and ovarian serouscystadenoma.

Examples of metabolic disorders which may be treated or prevented, inparticular treated, include, but are not limited to, diabetes orobesity.

Examples of blood disorders which may be treated or prevented, inparticular treated, include, but are not limited to, hemoglobinopathy,such as sickle cell disease or β-thalassemia.

Examples of cancers which may be treated or prevented, in particulartreated, include, but are not limited to, acoustic neuroma,adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g.,lymphangio sarcoma, lymphangioendothelio sarcoma. hemangio sarcoma),appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g.,cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinomaof the breast, papillary carcinoma of the breast, mammary cancer,medullary carcinoma of the breast), brain cancer (e.g., meningioma;glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchuscancer, carcinoid tumor, cervical cancer (e.g., cervicaladenocarcinoma), chordoma, choriocarcinoma, craniopharyngioma,colorectal cancer (e.g., colon cancer, rectal cancer, colorectaladenocarcinoma), epithelial carcinoma, ependymoma, endothelio sarcoma(e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma),endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophagealcancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma),Evving sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma),familiar hypereosinophiiia, gall bladder cancer, gastric cancer (e.g.,stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head andneck cancer (e.g., head and neck squamous cell carcinoma, oral cancer(e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g.,pharyngeal cancer, laryngeal cancer, nasopharyngeal cancer,oropharyngeal cancer)), hematopoietic cancers (e.g., leukemia such asacute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acutemyelocytic leukemia (AML) (e.g., B-cell AMI T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL. T-cell CLL); lymphoma suchas Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkinlymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma(DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., “Waldenstrom's macro globulinemia”), immunoblastie largecell lymphoma, hairy cell leukemia (HCL), precursor B-lymphoblast islymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma (MM)), heavy chain disease (e.g.,alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblast is tumors, immunocytic amyloidosis,kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cellcarcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignanthepatoma), lung cancer (e.g., bronchogenic carcinoma, non-small celllung cancer (NSCLC), squamous lung cancer (SLC), adenocarcinoma of thelung, Lewis lung carcinoma, lung neuroendocrine tumors: typicalcarcinoid, atypical carcinoid, small cell lung cancer

(SCLC), and large cell neuroendocrine carcinoma), leiomyosarcoma (LMS),mastocytosis (e.g., systemic mastocytosis), myelodysplasia syndromes(MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g.,polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloidmetaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathicmyelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilicleukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma,neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2,schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreaticneuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovariancancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarianadenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g.,pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm(IPMN), Islet cell tumors), penile cancer (e.g., Paget's disease of thepenis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT),prostate cancer (e.g., prostate adenocarcinoma), rectal cancer,rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamouscell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cellcarcinoma (BCC)), small bowel cancer (e.g., appendix cancer), softtissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma,malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma,fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat glandcarcinoma, synovioma, testicular cancer (e.g., seminoma, testicularembryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of thethyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer),urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget'sdisease of the vulva).

Examples of neurodegenerative diseases which may be treated orprevented, in particular treated, include, but are not limited to, motorneurone disease, progressive supranuclear palsy, corticobasaldegeneration. Pick's disease, Alzheimer s disease, AIDS-relateddementia, Parkinson's disease, amyotropic lateral sclerosis, retinitispigmentosa, spinal muscular atropy, and cerebellar degeneration.

Examples of cardiovascular diseases which may be treated or prevented,in particular treated, include, but are not limited to, cardiachypertrophy, restenosis, atherosclerosis, and glomerulonephritis.

Examples of inflammatory diseases which may be treated or prevented, inparticular treated, include, but are not limited to, inflammationassociated with acne, anemia (e.g., aplastic anemia, haemolyticautoimmune anaemia), rhinitis, asthma, arteritis (e.g., polyarteritis,temporal arteritis, periarteritis nodosa, Takayasu's arteritis),arthritis (e.g., crystalline arthritis, osteoarthritis, psoriaticarthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis andReiter's arthritis), upper respiratory tract disease, ankylosingspondylitis, amylosis. amyotrophic lateral sclerosis, autoimmunediseases, allergies or allergic reactions, atherosclerosis, bronchitis,bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronicobstructive pulmonary disease, diverticulitis, cermatomyositis, diabetes(e.g., type I diabetes mellitus, type 2 diabetes mellitus), a skincondition (e.g., psoriasis, eczema, eczema hypersensitivity reactions,burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barresyndrome, infection, ischaemic heart disease, Kawasaki disease,glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g.,migraine headaches, tension headaches), ileus (e.g., postoperative ileusand ileus during sepsis), idiopathic thrombocytopen is purpura,interstitial cystitis (painful bladder syndrome), gastrointestinaldisorder (e.g., selected from peptic ulcers, regional enteritis,diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinaldisorders (e.g., eosinophilic esophagitis, eosinophilic gastritis,eosinophilic gastroenteritis, eosinophilic colitis), gastritis,diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD),inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerativecolitis, collagenous colitis, lymphocytic colitis, ischaemic colitis,diversion colitis, Behcet's syndrome, indeterminate colitis) andinflammatory bowel syndrome (IBS)), lupus, morphea, myeasthenia gravis,myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigusvulgaris, pernicious aneaemia, peptic ulcers, polymyositis, primarybiliary cirrhosis, neuroinflammation associated with brain disorders(e.g., Parkinson's disease, Huntington's disease, and Alzheimer'sdisease), prostatitis, chronic inflammation associated with cranialradiation injury, pelvic inflammatory disease, reperfusion injury,regional enteritis, rheumatic fever, systemic lupus erythematosus,schleroderma, scierodoma, sarcoidosis, spondyloarthopathies, Sjogren'ssyndrome, thyroiditis, transplantation rejection, tendonitis, trauma orinjury (e.g., frostbite, chemical irritants, toxins, scarring, burns,physical injury), vasculitis, vitiligo and Wegener's granulomatosis.

In particular the inflammatory disease is an acute inflammatory disease(e.g., for example, inflammation resulting from infection). Inparticular the inflammatory disease is a chronic inflammatory disease(e.g., conditions resulting from asthma, arthritis and inflammatorybowel disease). The compounds may also be useful in treatinginflammation associated with trauma and non-inflammatory myalgia. Thecompounds may also be useful in treating inflammation associated withcancer.

Examples of autoimmune diseases which may be treated or prevented, inparticular treated, include, but are not limited to, arthritis(including rheumatoid arthritis, spondyloarthopathies, gouty arthritis,degenerative joint diseases such as osteoarthritis, systemic lupuserythematosus, Sjogren's syndrome, ankylosing spondylitis,undifferentiated spondylitis, Behcet's disease, haemolytic autoimmuneanaemias, amyotrophic lateral sclerosis, amylosis, multiple sclerosis,acute painful shoulder, psoriatic, and juvenile arthritis), asthma,atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skincondition (e.g., psoriasis, eczema, eczema hypersensitivity reactions,burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease,gastrointestinal disorder (e.g., selected from peptic ulcers, regionalenteritis, diverticulitis, gastrointestinal bleeding, eosinophilicgastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilicgastritis, eosinophilic gastroenteritis, eosinophilic colitis),gastritis, diarrhea, gastroesophageal reflux disease (GORD, or itssynonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease,ulcerative colitis, collagenous colitis, lymphocytic colitis, ischaemiccolitis, diversion colitis, Behcet's syndrome, indeterminate colitis)and inflammatory bowel syndrome (IBS)), and disorders ameliorated by agastroprokinetic agent (e.g., ileus, postoperative ileus and ileusduring sepsis; gastroesophageal reflux disease (GORD, or its synonymGERD); eosinophilic esophagitis, gastroparesis such as diabeticgastroparesis; food intolerances and food allergies and other functionalbowel disorders, such as non-ulcerative dyspepsia (NUD) and non-cardiacchest pain (NCCP, including costo-chondritis)).

In a particular embodiment, a provided compound may be useful in somaticcell reprogramming, such as reprogramming somatic cells into stem cells.In a particular embodiment, a provided compound may be useful in germcell development, and are thus envisioned useful in the areas ofreproductive technology and regenerative medicine.

Other diseases which may be treated or prevented, in particular treated,include, but are not limited to, ischemic injury associated myocardialinfarctions, immunological diseases, stroke, arrhythmia, toxin-inducedor alcohol related liver diseases, aspirin-sensitive rhinosinusitis,cystic fibrosis, cancer pain, and haematological diseases, for examplechronic anemia and aplastic anemia.

The compounds of the present invention may also have therapeuticapplications in sensitising tumour cells for radiotherapy andchemotherapy.

Hence the compounds of the present invention may be used as“radiosensitizer” and/or “chemosensitizer” or can be given incombination with another “radiosensitizer” and/or “chemosensitizer”.

The term “radiosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of thecells to ionizing radiation and/or to promote the treatment of diseaseswhich are treatable with ionizing radiation.

The term “chemosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of cellsto chemotherapy and/or promote the treatment of diseases which aretreatable with chemotherapeutics.

Several mechanisms for the mode of action of radiosensitizers have beensuggested in the literature including: hypoxic cell radiosensitizers(e.g., 2- nitroimidazole compounds, and benzotriazine dioxide compounds)mimicking oxygen or alternatively behave like bioreductive agents underhypoxia; non-hypoxic cell radiosensitizers (e.g., halogenatedpyrimidines) can be analogoues of DNA bases and preferentiallyincorporate into the DNA of cancer cells and thereby promote theradiation-induced breaking of DNA molecules and/or prevent the normalDNA repair mechanisms; and various other potential mechanisms of actionhave been hypothesized for radiosensitizers in the treatment of disease.

Many cancer treatment protocols currently employ radiosensitizers inconjunction with radiation of x-rays. Examples of x-ray activatedradiosensitizers include, but are not limited to, the following:metronidazole, misonidazole, desmethyImisonidazole pimonidazole.etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E₀₉, RB 6145,nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (lUdR),bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin,and therapeutically effective analogs and derivatives of the same.

Photodynamic therapy (PDT) of cancers employs visible light as theradiation activator of the sensitizing agent. Examples of photodynamicradiosensitizers include the following, but are not limited to:hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tinetioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines,phthalocyanines, zinc phthalocyanine, and therapeutically effectiveanalogs and derivatives of the same.

Radiosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof radiosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour with or withoutadditional radiation; or other therapeutically effective compounds fortreating cancer or other diseases.

Chemosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof chemosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour or other therapeuticallyeffective compounds for treating cancer or other disease. Calciumantagonists, for example verapamil, are found useful in combination withantineoplastic agents to establish chemosensitivity in tumor cellsresistant to accepted chemotherapeutic agents and to potentiate theefficacy of such compounds in drug-sensitive malignancies.

The compounds of the present invention might also reduce the risk ofcancer recurrence.

The invention relates to compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, for use as amedicament.

The invention relates to compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, for use in theinhibition of PRMT5 activity.

The compounds of the present invention can be “anti-cancer agents”,which term also encompasses “anti-tumor cell growth agents” and“anti-neoplastic agents”.

The invention relates to compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, for use in thetreatment of diseases mentioned above.

The invention relates to compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, for the treatment orprevention, in particular for the treatment, of said diseases.

The invention relates to compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, for the treatment orprevention, in particular in the treatment, of PRMT5 mediated diseasesor conditions.

The invention relates to compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, for the manufacture ofa medicament.

The invention relates to compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, for the manufacture ofa medicament for the inhibition of PRMT5.

The invention relates to compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, for the manufacture ofa medicament for the treatment or prevention, in particular for thetreatment, of any one of the disease conditions mentioned hereinbefore.

The invention relates to compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, for the manufacture ofa medicament for the treatment of any one of the disease conditionsmentioned hereinbefore.

The invention relates to compounds of Formula (I) and pharmaceuticallyacceptable addition salts, and solvates thereof, can be administered tomammals, preferably humans, for the treatment or prevention of any oneof the diseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I) andpharmaceutically acceptable addition salts, and solvates thereof, thereis provided a method of treating w arm-blooded animals, includinghumans, suffering from or a method of preventing warm-blooded animals,including humans, to suffer from any one of the diseases mentionedhereinbefore.

Said methods comprise the administration, i.e. the systemic or topicaladministration, preferably oral administration, of an effective amountof a compound of Formula (!) or a pharmaceutically acceptable additionsalt, or a solvate thereof, to warm-blooded animals, including humans.

Those of skill in the treatment of such diseases could determine theeffective therapeutic daily amount from the test results presentedhereinafter. An effective therapeutic daily amount would be from about0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg bodyweight, more in particular from 0.01 mg/kg to 25 mg/kg body weight,preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably fromabout 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1mg/kg body weight. A particular effective therapeutic daily amount mightbe from about 0.01 to 1.00 g twice a day (BID), more in particular 0.30to 0.85 g BID; even more in particular 0.40 g BID. The amount of acompound according to the present invention, also referred to here asthe active ingredient, which is required to achieve a therapeuticallyeffect will of course, vary on case-by-case basis, for example with theparticular compound, the route of administration, the age and conditionof the recipient, and the particular disorder or disease being treated.

A method of treatment may also include administering the activeingredient on a regimen of between one and four intakes per day. Inthese methods of treatment the compounds according to the invention arepreferably formulated prior to administration. As described hereinbelow, suitable pharmaceutical formulations are prepared by knownprocedures using well known and readily available ingredients.

The compounds of the present invention, that can be suitable to treat orprevent cancer or cancer-related conditions, may be administered aloneor in combination with one or more additional therapeutic agents.Combination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of Formula (I), apharmaceutically acceptable addition salt, or a solvate thereof, and oneor more additional therapeutic agents, as well as administration of thecompound of Formula (I), a pharmaceutically acceptable addition salt, ora solvate thereof, and each additional therapeutic agents in its ownseparate pharmaceutical dosage formulation. For example, a compound ofFormula (I), a pharmaceutically acceptable addition salt, or a solvatethereof, and a therapeutic agent may be administered to the patienttogether in a single oral dosage composition such as a tablet orcapsule, or each agent may be administered in separate oral dosageformulations.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition.

Accordingly, the present invention further provides a pharmaceuticalcomposition and, as active ingredient, a therapeutically effectiveamount of a compound of Formula (I), a pharmaceutically acceptableaddition salt, or a solvate thereof.

Accordingly, the present invention further provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and, asactive ingredient, a therapeutically effective amount of a compound ofFormula (I), a pharmaceutically acceptable addition salt, or a solvatethereof.

The carrier or diluent must be “acceptable” in the sense of beingcompatible with the other ingredients of the composition and notdeleterious to the recipients thereof.

For ease of administration, the subject compounds may be formulated intovarious pharmaceutical forms for administration purposes. The compoundsaccording to the invention, in particular the compounds of Formula (I)and pharmaceutically acceptable addition salts, and solvates thereof, orany subgroup or combination thereof may be formulated into variouspharmaceutical forms for administration purposes. As appropriatecompositions there may be cited all compositions usually employed forsystemically administering drugs.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound as the active ingredient iscombined in intimate admixture with a pharmaceutically acceptablecarrier, which carrier may take a wide variety of forms depending on theform of preparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable, inparticular, for administration orally, rectally, percutaneously, byparenteral injection or by inhalation. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed such as, for example, water, glycols, oils, alcohols andthe like in the case of oral liquid preparations such as suspensions,syrups, elixirs, emulsions and solutions; or solid carriers such asstarches, sugars, kaolin, diluents, lubricants, binders, disintegratingagents and the like in the case of powders, pills, capsules and tablets.Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit forms in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, for example, to aid solubility,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable solutions containinga compound of Formula (I), a pharmaceutically acceptable addition salt,or a solvate thereof, may be formulated in an oil for prolonged action.Appropriate oils for this purpose are, for example, peanut oil, sesameoil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters oflong chain fatty acids and mixtures of these and other oils. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. Also includedare solid form preparations that are intended to be converted, shortlybefore use, to liquid form preparations. In the compositions suitablefor percutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not introduce a significant deleterious effect on theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on, as an ointment. Acid or base addition salts ofcompounds of Formula (I) due to their increased water solubility overthe corresponding base or acid form, are more suitable in thepreparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage.

Unit dosage form as used herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such unit dosage forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,suppositories, injectable solutions or suspensions and the like, andsegregated multiples thereof.

In order to enhance the solubility and/or the stability of the compoundsof Formula (I) and pharmaceutically acceptable addition salts, andsolvates thereof, in pharmaceutical compositions, it can be advantageousto employ α-, β- or γ-cyclodextrins or their derivatives, in particularhydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin or sulfobutyl —P-cyclodextrin. Alsoco-solvents such as alcohols may improve the solubility and/or thestability of the compounds according to the invention in pharmaceuticalcompositions.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% b y weight, more preferablyfrom 0.1 to 70% b y weight, even more preferably from 0. 1 to 50% b yweight of the compound of Formula (I), a pharmaceutically acceptableaddition salt, or a solvate thereof, and from 1 to 99.95 b y weight,more preferably from 30 to 99.9% b y weight, even more preferably from50 to 99.9% by weight of a pharmaceutically acceptable carrier, allpercentages being based on the total weight of the composition.

As another aspect of the present invention, a combination of a compoundof the present invention with another anticancer agent is envisaged,especially for use as a medicine, more specifically for use in thetreatment of cancer or related diseases.

For the treatment of the above conditions, the compounds of theinvention may b e advantageously employed in combination with antibodybased immune cell redirection, for example T-cel1/neutrophilredirection. This can b e achieved for example by the use of bispecificmonoclonal antibodies or artificial T-cell receptors.

For the treatment of the above conditions, the compounds of theinvention may b e advantageously employed in combination with one ormore other medicinal agents, more particularly, with other anti-canceragents or adjuvants in cancer therapy. Examples of anti-cancer agents oradjuvants (supporting agents in the therapy) include but are not limitedto:

-   -   platinum coordination compounds for example cisplat in        optionally combined with amifostine, carboplatin or oxaliplatin;    -   taxane compounds for example paclitaxel, paclitaxel protein        bound particles (Abraxane™) or docetaxel;    -   topoisomerase I inhibitors such as camptothecin compounds for        example irinotecan, SN-38, topotecan, topotecan hcl;    -   topoisomerase 11 inhibitors such as anti-tumour        epipodophyllotoxins or podophyllotoxin derivatives for example        etoposide, etoposide phosphate or teniposide;    -   anti-tumour vinca alkaloids for example vinblastine, vincristine        or vinorelbinc;    -   anti-tumour nucleoside derivatives for example 5-fluorouracil,        leucovorin, gemcitabine, gemcitabine hcl, capecitabine,        cladribine, fludarabine, nelarabine;    -   alkylating agents such as nitrogen mustard or nitrosourea for        example cyclophosphamide, chlorambucil, carmustine, thiotepa,        mephalan (melphalan), lomustine, altretamine, busulfan,        dacarbazine, estramustine, ifosfamide optionally in combination        with mesna, pipobroman, procarbazine, streptozocin,        temozolomide, uracil;    -   anti-tumour anthracycline derivatives for example daunorubicin,        doxorubicin optionally in combination with dexrazoxane, doxil,        idarubicin, mitoxantrone. epirubicin, epirubicin hcl,        valrubicin;    -   molecules that target the IGF-1 receptor for example        picropodophilin;    -   tetracarcin derivatives for example tetrocarcin A;    -   glucocorticoids for example prednisone;    -   antibodies for example trastuzumab (HER2 antibody), rituximab        (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab,        pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab        tiuxetan, nofetumomab, panitumumab, tositumomab, CNTO 328;    -   estrogen receptor antagonists or selective estrogen receptor        modulators or inhibitors of estrogen synthesis for example        tamoxifen, fulvestrant, toremifene, droloxifene, faslodex,        raloxifene or letrazole;    -   aromatase inhibitors such as exemestane, anastrozole, letrazole,        testolactone and vorozole;    -   differentiating agents such as retinoids, vitamin D or retinoic        acid and retinoic acid metabolism blocking agents (RAMBA) for        example accutane;    -   DNA methyl transferase inhibitors for example azacytidine or        decitabine;    -   antifolates for example premetrexed disodium;    -   antibiotics for example antinomycin D, bleomycin, mitomycin C,        dactinomycin. carminomycin, daunomycin, levamisole, plicamycin,        mithramycin;    -   antimetabolites for example clofarabine, aminopterin, cytosine        arabinoside or methotrexate, azacitidine, cytarabine,        floxuridine, pentostatin, thioguanine;    -   apoptosis inducing agents and antiangiogenic agents such as        Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol,        HA 14-1, TW 37 or decanoic acid;    -   tubuline-binding agents for example combrestatin, colchicines or        nocodazole;    -   kinase inhibitors (e.g. EGFR (epithelial growth factor receptor)        inhibitors, MTKI (multi target kinase inhibitors), mTOR        inhibitors) for example flavoperidol, imatinib mesylate,        erlotinib, gefitinib, dasatinib, lapatinib, lapatinib        ditosylate, sorafenib, sunitinib, sunitinib maleate,        temsirolimus;    -   farnesy liransferase inhibitors for example tipifarnib;    -   historic deacetylase (HDAC) inhibitors for example sodium        butyrate, suberoylanilide hydroxamic acid (SAHA), depsipeptide        (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A,        vorinostat;    -   Inhibitors of the ubiquitin-proteasome pathway for example        PS-341, MLN 41 or bortezomib;    -   Yondelis;    -   Telomerase inhibitors for example telomestatin;    -   Matrix metalloproteinase inhibitors for example batimastat,        marimastat, prinostat or metastat.    -   Recombinant interleukins for example aldesleukin, denileukin        diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon        alfa 2b    -   MAPK inhibitors    -   Retinoids for example alitretinoin, bexarotene, tretinoin    -   Arsenic trioxide    -   Asparaginase    -   Steroids for example dromostanolonc propionate, megestrol        acetate, nandrolone (decanoate, phenpropionate), dexamethasone    -   Gonadotropin releasing hormone agonists or antagonists for        example abarelix. goserelin acetate, histrelin acetate,        leuprolide acetate    -   Thalidomide, lenalidomide    -   Mercaptopurine, mitotanc, pamidronate, pegademase, pcgaspargasc,        rasburicase    -   BH3 mimetics for example ABT-737    -   MEK inhibitors for example PD98059, AZD6244, CI-1040    -   colony-stimulating factor analogs for example filgrastim,        pegfilgrastim, sargramostim; erythropoietin or analogues thereof        (e.g. darbepoetin alfa); interleukin 11; oprelvekin;        zoledronate, zoledronic acid; fentanyl; bisphosphonate;        palifermin    -   a steroidal cytochrome P450 17alpha-hydroxylase-17.20-lyase        inhibitor (CYP17), e.g. abiraterone, abiraterone acetate    -   Glycolysis inhibitors, such as 2-deoxyglucose    -   mTOR inhibitors such as rapamycins and rapalogs, and mTOR kinase        inhibitors    -   PI3K inhibitors and dual mTOR/PI3K inhibitors    -   autophagy inhibitors, such as chloroquine and        hydroxy-chloroquine    -   antibodies that re-activate the immune response to tumors, for        example nivolumab (anti-PD-1), lambrolizumab (anti-PD-1),        ipilimumab (anti-CTLA4), and MPDL3280A (anti-PD-L1)

The present invention further relates to a product containing as firstactive ingredient a compound according to the invention and as furtheractive ingredient one or more anticancer agents, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of patients suffering from cancer.

The one or more other medicinal agents and the compound according to thepresent invention may be administered simultaneously (e.g. in separateor unitary compositions) or sequentially in either order. In the lattercase, the two or more compounds will be administered within a period andin an amount and manner that is sufficient to ensure that anadvantageous or synergistic effect is achieved. It will be appreciatedthat the preferred method and order of administration and the respectivedosage amounts and regimes for each component of the combination willdepend on the particular other medicinal agent and compound of thepresent invention being administered, their route of administration, theparticular tumour being treated and the particular host being treated.The optimum method and order of administration and the dosage amountsand regime can be readily determined by those skilled in the art usingconventional methods and in view of the information set out herein.

The weight ratio of the compound according to the present invention andthe one or more other anticancer agent(s) when given as a combinationmay be determined by the person skilled in the art. Said ratio and theexact dosage and frequency of administration depends on the particularcompound according to the invention and the other anticancer agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. A particular weight ratio for thepresent compound of Formula (l) and another anticancer agent may rangefrom 1/10 to 10/1, more in particular from 1/5 to 5/1, even more inparticular from 1/3 to 3/1.

The platinum coordination compound is advantageously administered in adosage of 1 to 500 mg per square meter (mg/m²) of body surface area, forexample 50 to 400 mg/m², particularly for cisplatin in a dosage of about75 mg/n{circumflex over (r)} and for carboplatin in about 300mg/n{circumflex over (r)} per course of treatment.

The taxane compound is advantageously administered in a dosage of 50 to400 mg per square meter (mg/n{circumflex over (r)}) of body surfacearea, for example 75 to 250 mg/n{circumflex over (r)}, particularly forpaclitaxel in a dosage of about 175 to 250 mg/n{circumflex over (r)} andfor docetaxel in about 75 to 150 mg/m² per course of treatment.

The camptothecin compound is advantageously administered in a dosage of0.1 to 400 mg per square meter (mg/n{circumflex over (r)}) of bodysurface area, for example 1 to 300 mg/n{circumflex over (r)},particularly for irinotecan in a dosage of about 100 to 350mg/n{circumflex over (r)} and for topotecan in about 1 to 2mg/n{circumflex over (r)} per course of treatment.

The anti-tumour podophyllotoxin derivative is advantageouslyadministered in a dosage of 30 to 300 mg per square meter (mg/m²) ofbody surface area, for example 50 to 250 mg/m², particularly foretoposide in a dosage of about 35 to 100 mg/n{circumflex over (r)} andfor teniposide in about 50 to 250 mg/n{circumflex over (r)} per courseof treatment.

The anti-tumour vinca alkaloid is advantageously administered in adosage of 2 to 30 mg per square meter (mg/n{circumflex over (r)}) ofbody surface area, particularly for vinblastine in a dosage of about 3to 12 mg/n{circumflex over (r)}, for vincristine in a dosage of about 1to 2 mg/n{circumflex over (r)}, and for vinorelbine in dosage of about10 to 30 mg/n{circumflex over (r)} per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered ina dosage of 200 to 2500 mg per square meter (mg/n{circumflex over (r)})of body surface area, for example 700 to 1500 mg/n{circumflex over (r)},particularly for 5-FU in a dosage of 200 to 500 mg/m{circumflex over(\)} for gemcitabine in a dosage of about 800 to 1200 mg/m² and forcapecitabine in about 1000 to 2500 mg/n{circumflex over (r)} per courseof treatment.

The alkylating agents such as nitrogen mustard or nitrosourea isadvantageously administered in a dosage of 100 to 500 mg per squaremeter (mg/m²) of body surface area, for example 120 to 200 mg/m²,particularly for cyclophosphamide in a dosage of about 100 to 500mg/n{circumflex over (r)}, for chlorambucil in a dosage of about 0.1 to0.2 mg/kg, for carmustine in a dosage of about 150 to 200 mg/m², and forlomustine in a dosage of about 100 to 150 mg/n{circumflex over (r)} percourse of treatment.

The anti-tumour anthracycline derivative is advantageously administeredin a dosage of 10 to 75 mg per square meter (mg/m²) of body surfacearea, for example 15 to 60 mg/n{circumflex over (r)}; particularly fordoxorubicin in a dosage of about 40 to 75 mg/n{circumflex over (r)}, fordaunorubicin in a dosage of about 25 to 45 mg/n{circumflex over (r)},and for idarubicin in a dosage of about 10 to 15 mg/n{circumflex over(r)} per course of treatment.

The antiestrogen agent is advantageously administered in a dosage ofabout 1 to 100 mg daily depending on the particular agent and thecondition being treated. Tamoxifen is advantageously administered orallyin a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day,continuing the therapy for sufficient time to achieve and maintain atherapeutic effect. Toremifene is advantageously administered orally ina dosage of about 60 mg once a day, continuing the therapy forsufficient time to achieve and maintain a therapeutic effect.Anastrozole is advantageously administered orally in a dosage of about 1mg once a day. Droloxifene is advantageously administered orally in adosage of about 20-100 mg once a day. Raloxifene is advantageouslyadministered orally in a dosage of about 60 mg once a day. Exemestane isadvantageously administered orally in a dosage of about 25 mg once aday.

Antibodies are advantageously administered in a dosage of about 1 to 5mg per square meter (mg/n{circumflex over (r)}) of body surface area, oras known in the art, if different. Trastuzumab is advantageouslyadministered in a dosage of 1 to 5 mg per square meter (mg/m²) of bodysurface area, particularly 2 to 4 mg/n{circumflex over (r)} per courseof treatment. These dosages may be administered for example once, twiceor more per course of treatment, which may be repeated for example every7, 14, 21 or 28 days.

The following examples illustrate the present invention. In case nospecific stereochemistry is indicated for a stereocenter of a compound,this means that a mixture of the R and the S enantiomers was obtained.In case more than 1 stereocenter is present in a structure, eachstereocenter for which no specific stereochemistry is indicated wasobtained as a mixture of R and S.

The skilled person will realize that typically after a columnpurification, the desired fractions were collected and the solvent wasevaporated to obtain the desired compound or intermediate.

EXAMPLES

Hereinafter, the term “rt”, “r.t.” or “RT” means room temperature; “Me”means methyl; “MeOH” means methanol; “Et” means ethyl; “EtOH” meansethanol; “NaH” means sodium hydride; “Boc” means tert-butoxycarbonyl;“(Boc)20” means tert-butoxycarbonyl anhydride; “EtOAc” means ethylacetate; “Et₂O” means di-ethylether; “Et3N” means triethylamine: “DCM”means dichloromethane; “q.s.” means quantum sufficit; “Int.” meansintermediate; “MeCN” or “ACN” means acetonitrile; “DMF” means/V,/V-dimethyl formamide; “PdCl₂(dppf)” means[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); “THF” meanstetrahydrofuran; “IPA” or “iPrOH” means 2-propanol; “LC” means liquidchromatography; “LCMS” means Liquid Chromatography/Mass spectrometry;“HPLC” means high-performance liquid chromatography; “TFA” meanstrifluoroacetic acid; “RP” means reversed phase; “min” means minute(s);“h” means hour(s); “v/v” means volume per volume; “Celite®” meansdiatomaceous earth; “DMSO” means dimethyl sulfoxide; “SFC” meansSupercritical Fluid Chromatography; “DIPE” means diisopropyl ether;“DIPEA” means N,N-diisopropylethylamine; “PPI13” meanstriphenylphosphine; “Pd₂(dba)₃ meansTris(dibenzylideneacetone)dipalladium; “DIAD” means diisopropylazodicarboxylate; “TBAF” means tetrabutylammonium fluoride; “psi” meanspound-force per square inch; “eq.” means equivalent(s); “Pd(OAc)₂” meanspalladium(II) acetate; “DMAP” means ₄-(dimethylamino)pyridine; “t-BuOK”or “KOtBu” means potassium tert-butoxide; “Dess-Martin periodinane”means 1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one; “TBDMSC1”means tert-Butyldimethylsilyl chloride; “Bn” means benzyl; “9-BBN” means9-Borabicyclo[3.3.1Jnonane; “Pd-118” meansDichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II); “Tf₂0”means triflic anhydride; “TBDMS” means tertButyl dimethylsilyl; “TMSCl”trimethylsilyl chloride; “BuLi” means n-butyllithium; “aq.” meansaqueous; “NaOMe” means sodium methoxide; “tBuOH” means tert-butylalcohol; “n-BuOH” means n-butanol; “NaHMDS” means sodiumbis(trimethylsilyl)amide; “Diazald®” meansN-Memyl-N-(/48-tolylsulfonyl)nitrosamide; “Ts” or “Tos” means tosyl(p-to]uenesulfonyl),

Intermediates and compounds containing a double bond with substituentswhich may be in the E or the Z configuration are show in one particularconfiguration in the experimental part below. However, unless explicitlyindicated by E or Z, it was not determined if these intermediates andcompounds were obtained in the E or Z configuration or as a mixture ofboth configurations. For example intermediates 86, 90, 9.1, and 139might be in the E or Z configuration or might be mixtures thereof.

For example compounds 30, 34, 35, 36, and 37, were obtained in the Econfiguration and are explicitly indicated as such E in the experimentalpart below.

A. Preparation of Intermediates Example A1 Preparation of Intermediate I

To a mixture of 4,6-dichloro-5-(2,2-diethoxyethyi)pyrimidine (14.0 g,52.8 mmol) and(1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diolhydrochloride (10.7 g, 58.1 mmol) in propan-2-ol/H₂0 (208 mL, 7:1), wasadded Et3N (13.4 g, 132 mmol) in one portion at 25° C. under N2. Themixture was stirred at 90° C. for 23 hours. The mixture was cooled to50° C. and 4M HCl (24 mL, 106 mmol) was added slowly. The residue wasthen stirred at 50° C. for 2 hours. The reaction mixture was cooled to25° C. and NaHC0₃ (14 g, 100 mmol) was added slowly. Ethyl acetate (230mL) was added, followed by the addition of a half-saturated NaHC0₃solution (q.s.). The organic phase was isolated and the aqueous phasewas extracted with ethyl acetate (230 mL×2). The combined organic phaseswere dried with anhydrous MgS0₄, filtered and concentrated in vacuum toafford intermediate I as yellow solid (17.4 g, quantitative yield in 2steps). The crude product was directly used as such in the next reactionstep without further purification.

Example A2 Preparation of Intermediate 2

To a mixture of intermediate I (17.4 g, 52.7 mmol) in acetone (250 mL)was added 2,2-dimethoxypropane (11.0 g, 105 mmol) and TsOH.H₂0 (908 mg,5.27 mmol) in one portion at 25° C. under N2. The mixture was stirred at60° C. for ₂ hours. The mixture was cooled to 25° C. and the solutionwas partially concentrated in vacuum, quenched by slow addition ofsaturated NaHCO₃ (100 mL) and then extracted with ethyl acetate (100mL×3). The combined organic phases were washed with saturated brine (100mL), dried with anhydrous MgSC{circumflex over ( )}, filtered andconcentrated in vacuum. The residue was purified by flash chromatographyon silica gel (gradient elution: DCM/Ethyl acetate from 1/0 to 2/1) toafford intermediate 2 as light yellow gum (15.5 g, 89% yield).

Example A3 Preparation of Intermediate 3

To a mixture of intermediate 2 (2.85 g, 8.8 mmol) in DCM (130 mL) wasadded Dess-Martin periodinane (4.85 g, 11.4 mmol) at 0° C. under N₂. Themixture was stirred at room temperature for ₂ hours. The mixture wastreated with Na₂S₂O₃ (15 g) dissolved in a saturated NaHCO₃ solution (65mL) and stirred for another 30 min. The layers were separated and theaqueous phase was extracted with DCM (50 mL×3). The combined organicphases were washed with a saturated NaHC0₃ solution (65 mL) dried withanhydrous MgSOi, filtered and concentrated in vacuum to afford crudeintermediate 3 (2.9 g) which was directly used in the next reaction stepwithout further purification.

Example A4 Preparation of Intermediate 4

Method 1

To a mixture of mcthyltriphenylphosphonium bromide (4.87 g, 13.62 mmol)in THF (500 niL) was added t-BuOK (1.1.4 mL, 1M in THF, 1.27g, 11.35mmol) dropwise at 0° C. under N₂. The suspension was turned to brightyellow and stirred at 0° C. for 0.5 h and then warmed to 25° C. for 0.5h. The mixture was cooled to −40° C. A solution of intermediate 3 (1.46g, theoretically 4.54 mmol) in THF (130 mL) was added drop-wise and thenstirred at −20° C. for 1 h, after this, the mixture was warmed to 25° C.for 2h. To the mixture was added saturated NH4c (300 ml) and the mixturewas stirred for 10 min. The layers were separated and the aqueous phasewas extracted with DCM (300 mL×2). The combined organic phases werewashed with saturated brine (500 mL), dried with anhydrous MgS0₄,filtered and concentrated in vacuum. The residue was purified by silicagel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Gradienteluention: From 0% to 15% of Ethyl acetate/Petroleum ether). The desiredfractions were collected and the solvent was evaporated. Intermediate 4was obtained as an off-white solid (530 mg, 36% yield).

Method 2

A solution of intermediate 3 (10.0 g, theoretically 31.1 mmol) in THF(100 mL) was added dropwise under N₂ over a period of 30 minutes to abis(iodozincio)methane solution in THF (180 mL, 0.31M, 55.9 mmol,prepared according to the procedure described in Tetrahedron 2002, 58,8255-8262), stiffing was continued until complete conversion(approximately 2 hours). The reaction mixture was quenched by the slowaddition of a saturated aqueous NH₄C1 solution, during which saltformation was observed. Prior to extraction (EtOAc, 2×200 mL), the saltswere dissolved again by the addition of an aqueous ammonia solution(25%). The combined organic phases were washed with an aqueous sodiumbisulfite solution and brine, dried with anhydrous MgSOi, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography (eluent: dichloromethane/EtOAc 95/5) to provideintermediate 4 as an off-white solid (6.9 g, 66%).

Method 3 Step 1 Preparation of Intermediate 5

Acetylacetonatobis(ethylene)rhodium(I) (0.837 g, 3.24 mmol) and(R)—N,N-dimethyldinaphtho[2. 1-D: r.2′-F][1,3,2]dioxapho.sphepin-4-amine(2.91 g, 8.1 1 mmol) were dissolved in EtOH (625 mL) under nitrogenatmosphere. The mixture was stirred at room temperature and flushedthrough with nitrogen gas for 15 minutes. Then (−)-(3AR,6AR)-3A,6A-dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one (25 g, 162.16mmol) and potassium vinyltrifluoroborate (45.73 g, 324.33 mmol) wereadded and then the reaction mixture was stirred and refluxed for 4hours. The reaction mixture (suspension) was cooled down to roomtemperature. The precipitate was filtered off over a pad of Celite® andwashed with ethanol. The solvents of the filtrate were evaporated. 1Lheptane was added to the residue. The resulting suspension was filteredoff over a pad of Celite® and washed with heptanes resulting in a darkbrown solid residue. The filtrate was washed three times with 300 mLNH₄OH, washed with brine, dried with MgS0₄, filtered and the solventsof the filtrate evaporated yielding intermediate 5 (16.18 g, 51% yield).

Step 2 Preparation of Intermediate 6

A solution of intermediate 5 (16.18 g, 82.58 mmol) in THF (200 mL) wasadded dropwise to a stirred solution of lithium aluminum hydride in THF(24.78 mL, 1M, 24.78 mmol) in THF (400 mL) at −78° C. under nitrogenatmosphere. The reaction mixture was stirred at −78° C. under nitrogenatmosphere for 30 minutes. The reaction was quenched by the dropwiseaddition of acetone (6. 1 mL) followed by 50 mL water at −78° C. Afteraddition the reaction mixture was allowed to warm up to room temperatureand then 400 mL EtOAc was added. The mixture was shaken vigorously. Theorganic layer was separated, washed three times with water, washed withbrine, dried with Mg SO₄, filtered and the solvents of the filtrateevaporated. The residue was dissolved in ethyl acetate and purified overa 5102 column, type Grace Reveleris SRC, 80 g. Si 40, on an Armen Spot I1Ultimate purification system using ethyl acetate and heptane as eluentin a gradient starting from 100% heptane and ending with 50% heptane and50% ethyl acetate. The fractions containing product were combined andthe solvents were evaporated yielding intermediate 6 (10.77 g, 71%yield).

Step 3 Preparation of Intermediate 7

A solution of Tf₂0 (13.3 mL, 80.9 mmol) in DCM, anhydrous (60 ml) wasadded dropwise to a mixture of intermediate 6 (9.94 g, 53.95 mmol) andpyridine, anhydrous (85 mL) in DCM, anhydrous (140 mL) at 0° C. Thereaction mixture was stirred for 30 minutes and then 75 mL cold waterwas added. The layers were separated and the organic layer was washedthree times with 75 ml, water, dried with MgSOt, filtered and thesolvents evaporated and co-evaporated with 200 ml, toluene. The residuewas dissolved in heptane and ethyl acetate and purified over a Si0₂column, type Grace Reveleris SRC, 40 g, Si 40, on an Armen Spot11Ultimate purification system using ethyl acetate and heptane as eluentin a gradient starting from 100% heptane and ending with 50% heptane and50% ethyl acetate. The fractions containing product were combined andthe solvents were evaporated yielding intermediate 7(13.0 g, 67%>yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 7using the appropriatestarting materials (Table 22)

TABLE 22 Int. structure Starting materials  97

intermediate 96 116

intermediate 115

Step 4 Preparation of Intermediate 8

A mixture of 4-chloro-7H-pyrrolo [2,3-D]pyrimidine (100 g, 651 mmol) andKOtBu (73.07 g, 65.1 mmol) in THF (1 L) was stirred at room temperaturefor 45 minutes until a clear solution was obtained. The solvents wereevaporated. The residue was triturated in DIPE. The white solids werefiltered off and dried in vacuo at 30° C. yielding intermediate 8 (112.6g, 90% yield).

Step 5 Preparation of Intermediate 4

A solution of intermediate 7(13 g. 41.1 mmol) in DMF (50 mL) was addeddropwise to a stirred solution o intermediate 8 (7.88 g, 41.1 mmol) inDMF (150 mL) at 0° C. After addition the reaction mixture was allowed towarm to room temperature and was then stirred for 18 hours. Anadditional amount of intermediate 8 (1.57 g, 8.22 mmol) was added. Thereaction mixture was stirred at room temperature for 2 hours. Thereaction mixture was poured out into a beaker with ice and water(−0.51). The resulting suspension was stirred for 2 hours and thenfiltered off. The filter cake was washed three times with water and thendried in vacuo at 50° C. yielding intermediate 4 as a white solid (8.75g, 65% yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 4 using the appropriatestarting materials (Table 23)

TABLE 23 Starting Int. structure materials  98

intermediate  97 117

intermediate 116

Example A5 Preparation of Intermediate 9

A solution of intermediate 4 (18.3 g. 57.22 mmol) in a mixture ofaqueous ammonia (25%, 100 ml) and THF (100 ml) was heated in a sealedmetal pressure vessel at 110° C. until complete conversion (−16 h). Thereaction mixture was allowed to cool to room temperature, after whichethyl acetate and brine were added. Both layers were separated, thewater layer was extracted once with ethyl acetate. The combined organicphases were washed with brine, dried with anhydrous MgS0₄, filtered andconcentrated in vacuum to give intermediate 9 as a light yellow solid(17.2 g, 100% yield), which was used in the next reaction step withoutfurther purification.

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 9 using the appropriatestarting materials (Table 24)

TABLE 24 Starting Int. structure materials  99

intermediate  98 118

Intermediate 117

Example A 31 Preparation of Intermediate 96

A solution of cuprous iodide (43.7 g, 228 mmol) and lithium chloride(9.68 g, 228 mmol) in THF (320 mL) was stirred for 5 minutes at roomtemperature before cooling down to −78° C. under nitrogen atmosphere.Allyl magnesium bromide, 1M in Et2O (220 mL, 1M, 220 mmol) was added tothe solution dropwise over 20 minutes. After the reaction was stirredfor 30 minutes, TMSC1 (30 mL, 235 mmol) and hexamethylphosphoramide (42mL, 241 mmol) were added, followed by the dropwise addition of(−)-(3AR,6AR)-3A,6A-dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one(12.8 g, 83.0 mmol) in THF (1.10 mL). After addition the reactionmixture was stirred for 2 hours, warmed to 0° C. and quenched with asaturated aqueous NH4CI solution (100 mL). After addition of EtOAc (1L), the organic layer was separated, washed with water (200 mL) andbrine (200 mL), then dried over MgSOt. The solvent was evaporated underreduced pressure. The residue was purified over a 5102 column, typeGrace Reveleris SRC, 180 g. Si 40, on a Grace Reveleris X2 purificationsystem using heptane and ethyl acetate as eluents in a gradient startingfrom 100% heptane to 70% heptane and 30% ethyl acetate. The fractionscontaining product were combined and the solvents were evaporatedyielding intermediate 95 (8.00 g, 47% yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 95 using the appropriatestarting materials (Table 25)

TABLE 25 Int. structure Starting materials 114

(−)-(3AR,6AR)-3A,6A- dihydro-2,2-dimethyl- 4H-cyclopenta-l, 3-dioxol-4-one and 3-butenylmagnesium bromide

A solution intermediate 95 (8 g, 39.5 mmol) in THF (40 niL) was addeddropwise to a stirred solution of lithium bromide, 2M in THF (5.931 mL,2 M, 11.86 mmol) in THF (40 ml) at 0° C. under nitrogen atmosphere.After addition the reaction mixture was stirred at room temperature for2 hours. The reaction was quenched by the addition of 8 ml, waterfollowed by 15 mL aqeuous NaOH (IN), and again by 8 mL water. Theresulting solid was filtered off and the solvents of the filtrate werediluted with ethyl acetate. The organic layer was washed with water,washed with brine, dried with MgSO.4, filtered and the solvents of thefiltrate evaporated yielding intermediate 96 (7.41 g, 92% yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 96 using the appropriatestarting materials (Table 26)

TABLE 26 Int. structure Starting materials 115

Intermediate 114

Example A 26 Preparation of Intermediate 42 Step 1 Preparation ofIntermediate 39

Intermediate 2 (10 g, 30.5 mmol) was stirred in a mixture of THF (100ml) and aq. NH4OH 28% (100 ml) at 120° C. for two days in an autoclave.The volatiles were evaporated in vacuo. The aqueous layer was extractedseveral times with DCM/MeOH 90/10. The combined organic layers wereconcentrated under reduced pressure. The crude was redissolved in aminimum amount of MeOH, to which toluene was added. The obtainedsolution was concentrated again, and this process was repeated two timesuntil intermediate 39 (10.2 g, 100% yield) was obtained as a solidproduct which was used as such in the next step.

Step 2 Preparation of Intermediate 40

A solution of TBDMSC1 (7.6 g, 50.2 mmol, 1.5 eq.) in DMF (50 mL) wasdropwise added into a reaction flask charged with intermediate 39 (10.2g, 33.5 mmol), imidazole (4.6 g, 67.0 mmol, 2.0 eq.) and DMF (120 mL).The resulting reaction mixture was stirred overnight at roomtemperature. Water was added and extraction was carried out with diethylether. The combined organic layers were washed with water, dried withMgSC{circumflex over ( )}, and concentrated under reduced pressure togive intermediate 40 (10.4 g, 74%>yield).

Step 3 Preparation of Intermediate 41

A solution of (Boc)₂O (20.0 g, 86.9 mmol, 3.5 eq.) in THF (40 mL) wasadded dropwise into a reaction flask charged with intermediate 40 (10.4g, 24.8 mmol), DMAP (607 mg, 5.0 mmol, 0.2 eq.) and THF (85 mL). Theresulting reaction mixture was stirred at room temperature for 4 h.Next, TBAF in THF (1 M, 42.2 mL, 42.2 mmol, 1.7 eq.) was added dropwiseand stirring was continued until complete conversion was observed. Thereaction mixture was poured into water and extracted once with diethylether. The organic layer was separated, washed with brine, dried withMgS0₄, and concentrated in vacuo. The crude product was purified bysilica chromatography (30% to 0% gradient of heptane in ethyl acetate)to give intermediate ¥1 (12.1 g, 96% yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 41 using the appropriatestarting materials (Table 27)

TABLE 27 Int. structure Starting materials 143

Intermediate 2

Step 4 Preparation of Intermediate 42

p-Toluenesulfonyl chloride (5.1 g, 26.7 mmol) was added portion wise toa solution of intermediate 41 (9.0 g, 17.8 mmol), Et3N (4.5 g, 44.5mmol, 2.5 eq.) and DMAP (218 mg, 1.8 mmol, 0.1 eq.) in CH2CI2 (50 mL) at0° C. The reaction mixture was stirred at room temperature overnight.Water was added, the organic layer was separated, and the aqueous layerwas extracted with CH2CI2. The combined organic layers were washed withbrine, dried with MgS0₄, and concentrated under reduced pressure. Thecrude product was purified by silica chromatography (5% EtOH in CH2CI2)to give intermediate 42 (10.6 g, 90% yield).

Example A6 Preparation of Intermediate 13 Step 1 Preparation ofIntermediate 10

A solution of benzyl alcohol (18.2 g, 168 mmol, 1.0 eq.) in DMF (100 mL)was added dropwise to suspension of NaH (60% dispersion in mineral oil,6.5 g, 168 mmol, 1.0 eq.) in DMF (300 mL) under a nitrogen atmosphere.The reaction mixture was stirred at room temperature for an extra 30minutes. A solution of 2,4-dichloropyridine (24.9 g, 168 mmol, 1.0 eq.)in DMF (100 mL) was added dropwise. The reaction mixture was stirred for2 h, after which an additional portion of NaH (60% dispersion in mineraloil, 1.3 g, 33.6 mmol, 0.2 eq.) was added. Stirring was continued untilcomplete conversion. Upon completion, the reaction mixture was quenchedby the slow addition of water, and extracted with diethyl ether. Thecombined organic phases were dried with MgS0₄ and concentrated underreduced pressure. The crude product was suspended in heptane, filteredand dried under high vacuum to give intermediate 10 (19.3 g, 52% yield).

Step 2 Preparation of Intermediate 11

LiHMDS (105.4 mL, 1 M solution in THF, 105.4 mmol) was added to asolution of intermediate 10 (19.3 g, 87.9 mmol), Pd₂(dba)₃ (2.0 g, 2.2mmol, 0.025 eq.) and 2-dicyclohexylphosphinobiphenyl (2.5 g, 5.2 mmol,0.06 eq.) in anhydrous THF (90 mL) under a nitrogen atmosphere, theresulting mixture was stirred at 65° C. for 1 h. The reaction was thenallowed to cool to room temperature and IN aqueous HCl was added.Following 5 min of vigorous stirring, the reaction mixture wasneutralized with saturated Na2CC″3 and extracted with CH2CI2. Thecombined organic phases were dried over MgS04 and concentrated underreduced pressure. The crude product was suspended in isopropyl ether andstirred for 15 min at reflux temperature, after which it was allowed tocool to room temperature overnight. The precipitate was filtered off anddried under high vacuum to give intermediate 11 (14.7 g, 82% yield).

Step 3 Preparation of Intermediate 12

Chloroacetone (1.75 mL, 22.0 mmol, 1.1 eq.) was added dropwise to asolution of intermediate 11 (4.0 g, 20.0 mmol) in EtOH (20 mL). Thereaction mixture was stirred at reflux temperature overnight. Theresidue obtained after concentration of the reaction mixture underreduced pressure, was taken up in a mixture of ethyl acetate and water.The organic layer was separated and the water layer was furtherextracted with CH2CI2 (+MeOH), the combined organic phases (ethylacetate and CH2CI2 (+MeOH)) were concentrated under reduced pressure.The crude product was purified by silica chromatography (1% to 6%gradient of MeOH in CH2CI2) to give intermediate 12 (1.95 g, 42% yield).

Step 4 Preparation of Intermediate 13

A solution of intermediate 12 (2.2 g, 9.2 mmol) in methanol washydrogenated under atmospheric pressure for 2 h with Pd (10%>on carbon,491 mg, 0.46 mmol, 0.05 eq.) as catalyst. The reaction mixture wasfiltered over Celite® and the filtrate concentrated under reducedpressure to give intermediate 13 (1.4 g, 100% yield) as a brown solid.

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 12 and intermediate 13using the appropriate starting materials (Table 1)

TABLE 1 Int. structure Starting materials 14

intermediate 11 and 1-bromo-3,3,3- trifluoroacetone

Example A7 Preparation of Intermediate 18 Step 1 Preparation ofIntermediate 15

A mixture intermediate 11 (5.0 g, 25.0 mmol) and (BocbO (6.0 g, 27.5mmol, 1.1 eq.) in tBuOH (55 mL) was stirred at 50° C. for 1 h. Thereaction mixture was cooled to room temperature and diluted withethanol, the precipitate was filtered off and dried under high vacuum togive intermediate 15 (6.0 g, 80% yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 15 and using theappropriate starting materials (Table 2)

TABLE 2 Int. structure Starting materials 19

2-amino-4- bromopyridine 22

2-amino-5-fluoro-4- bromopyridine 25

2-amino-4-bromo-5- chloropyridine

Step 2 Preparation of Intermediate 16

To a solution of intermediate 15 (6.0 g, 20.0 mmol) in anhydrous DMF (80mL) was added NaH (1.1 g, 60% dispersion in mineral oil, 30.0 mmol, 1.4eq.) in portions at room temperature under a nitrogen atmosphere. Uponcomplete addition, the reaction mixture was stirred for an extra 10 minPropargyl bromide (3.1 mL, 30.0 mmol, 1.4 eq.) was added and stirringwas continued until complete conversion. The reaction was quenched bythe addition of water and extracted with diethyl ether. The combinedorganic phases were washed with water, dried with MgSC{circumflex over( )} and concentrated under reduced pressure. The crude product waspurified by silica chromatography (0% to 1.5% gradient of MeOH inCH₂C1₂) to give intermediate 16 (4.9 g, 72.5% yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 16 and using theappropriate starting materials (Table 3)

TABLE 3 Int. structure Starting materials 20

intermediate 19 23

intermediate 22 26

intermediate 25

Step 3 Preparation of Intermediate 17

KOtBu (1.9 g, 17.0 mmol, 1.2 eq.) was added to a solution ofintermediate 16 (4.8 g, 14.2 mmol) in THF (145 mL). The reaction mixturewas stirred at room temperature until complete conversion (typically ca.30 min). Water was added and extraction was carried out with ethylacetate. The combined organic phases were dried with MgSO₄ andconcentrated under reduced pressure. The product was purified by silicachromatography (1% to 4% gradient of MeOH in CH2C 12) to giveintermediate 17 (2.1 g, 62% yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 17 and using theappropriate starting materials (Table 4)

TABLE 4 Int. structure Starting materials 21

intermediate 20 24

intermediate 23 27

intermediate 26

Step 4 Preparation of Intermediate 18

A solution of 4 intermediate 17 (2. 1 g, 88 mmol) in methanol washydrogenated under atmospheric pressure for 2 h with Pd (10% on carbon,470 mg, 0.44 mmol, 0.05 eq.) as catalyst. The reaction mixture wasfiltered over Celite® and the filtrate concentrated under reducedpressure to give intermediate 18 (1.27 g, 97% yield).

Example A8 Preparation of Intermediate 29 Step 1 Preparation ofIntermediate 28

To an ice-cold mixture of 2-amino-4-bromo-3-chloropyridine (4.5 g, 2.1.7mmol) and (BochO (5.9 g, 26.0 mmol, 1.2 eq.) in anhydrous THF (165 mL)under nitrogen, was added dropwise NaHMDS (27. 1 mL of a 2 M solution inTHF, 54.2 mmol, 2.5 eq.). The resulting suspension was allowed to warmto room temperature and stirred until complete conversion (typically ca.1 h). Anhydrous DMF (165 mL) was added, followed by the addition ofpropargyl bromide (3.4 mL, 30.4 mmol, 1.4 eq.). The reaction mixture wasstirred overnight, quenched by the addition of water, and extracted withether. The combined organic phases were washed with water, dried withMgSOi and concentrated under reduced pressure to give crude product. Theproduct was purified by silica chromatography (10% ethyl acetate inheptane) to give intermediate 28 (6.4 g, 85% yield).

Step 2 Preparation of Intermediate 29

KOtBu (2.6 g, 23.1 mmol, 1.25 eq.) was added to a solution ofintermediate 28 (6.4 g, 18.5 mmol) in THF (90 mL). The reaction mixturewas stirred at room temperature until complete conversion (typically ca.30 min). Water was added and extraction was carried out with ethylacetate. The combined organic phases were dried with MgSC{circumflexover ( )} and concentrated under reduced pressure. Intermediate 29 (565mg, 12.5% yield) was isolated after two successive purifications bysilica chromatography (first run: 0% to 1.5% gradient of MeOH in CH2CI2,second run: 50%>ethyl acetate in heptane).

Example A9 Preparation of Intermediate 32 Step 1 Preparation ofIntermediate 30

A solution of 2-amino-4-bromopyridine (10.0 g, 57.8 mmol) and2-bromomalonaldehyde (10.5 g, 69.4 mmol, 1.2 eq.) in EtOH (200 mL) wasstirred at reflux temperature overnight. The reaction mixture wasallowed to cool to room temperature and concentrated under reducedpressure. The crude product was suspended in CH2CI2, the precipitate wasfiltered off and dried under high vacuum to give intermediate 30 (8.8 g,67% o yield), which was used as such in the next step.

Step 2 Preparation of Intermediate 31

A reaction flask charged with methyltriphenylphosphonium bromide (30 g,84.0 mmol, 1.9 eq.) and THF (450 mL), was cooled to −78° C. To this, asolution of KOtBu in THF (1M, 111 mL, 111 mmol, 2.5 eq.) was added andthe resulting suspension was stirred at −78° C. for 30 min A solution ofintermediate 30 (10 g, 44.4 mmol) in THF (50 mL) was added dropwise, thereaction mixture was stirred at −78° C. for 2 h, after which it wasallowed to warm to room temperature and stirred for an extra 2 h. Asaturated NH4CI was used for quenching and extraction was carried outwith CH2CI2, the combined organic phases were washed with brine, driedwith Na2SO₄ and concentrated under reduced pressure. The product waspurified by silica chromatography (5% to 100% gradient of ethyl acetatein petroleum ether) to give intermediate 31 as a white solid (6.4 g, 85%yield).

Step 3 Preparation of Intermediate 32

Intermediate 3/(1.1g, 4.5 mmol) was dissolved in an etherealdiazomethane solution (400 mL), freshly prepared from Diazald® (20 g, 93mmol, 20.0 eq.). The reaction mixture was cooled in an ice-bath andPd(OAc)2 (100 mg, 0.44 mmol, 0.1 eq.) was added. The reaction mixturewas stirred at room temperature overnight. The volatiles were removedunder reduced pressure, and the desired product was isolated by silicachromatography (5% to 100% gradient of ethyl acetate in petroleumether). A final purification by preparative reversed phase HPLC Columntype: Kromasil 150×25 mm, IOμιη, Condition: A: water (0.05% ammoniahydroxide v/v); B: MeCN at the beginning: A (61%) and B (39%); at theend: A: (61%) and B (39%), Gradient Time (min) 8; 100% B Hold Time(min)2; Flow Rate(ml/min) 30, yielded intermediate 32 as a white solid (160mg, 15% yield).

Example A10 Preparation of Intermediate 34 Step 1 Preparation ofIntermediate 33

A solution of Carbamic acid, N-(7-bromoimidazo[1,2-a]pyridin-2-yl)-,1,1-dimethylethyl ester (740 mg, 2.37 mmol) in methanolic hydrochloricacid (15 mL of a 4 M solution, 60 mmol, 25 eq.) was stirred at roomtemperature for 2 h. The reaction mixture was concentrated under reducedpressure, the resulting residue was basified with aqueous ammonia andextracted with ethyl acetate, the combined organic phases were driedwith Na₂S0₄ and concentrated under reduced pressure to give intermediate33 as a white solid (500 mg, 99% yield).

Step 2 Preparation of Intermediate 34

Acetyl chloride (201 μL, 2.83 mmol, 1.2 eq.) was added to a solution ofintermediate 33 (500 mg, 2.36 mmol) and Et3N (492 μL, 3.54 mmol, 1.5eq.) in CH₂C1₂ at 0° C., the resulting reaction mixture was stirred for30 min at 0° C. Water was added, the organic layer was separated and thewater layer was extracted with CH₂C1₂. The combined organic phases werewashed with brine, dried with Na₂S0₄ and concentrated under reducedpressure to give intermediate 34 (700 mg, 97% yield).

Example A 11 Preparation of Intermediate 35

NaH 60% in mineral oil (82 mg, 2 mmol) was added portionwise into thesolution of 1H-pyrrolo[3,2-6]pyridine, 2-iodo-(500 mg, 2 mmol) in DMF(20 ml) at 0° C. under N2 atmosphere. The mixture was stirred for 0.5hours. Then dimethylsulfate (0.32 g, 2.54 mmol) was added drop-wise intothe mixture over 30 minutes. Then the mixture was stirred at roomtemperature for 2 hours. The mixture was treated with water and wasextracted by ethyl acetate. The organic layer was filtered, washed withbrine and dried over Na2SO₄. The organic phase was concentrated toafford intermediate 35 (400 mg, 57% yield) as a yellow solid.

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 35 using the appropriatestarting materials (Table 5)

TABLE 5 Int. structure Starting materials 36

1H-pyrrolo[3,2-b] pyridine, 6-bromo-2- iodo-

Example A 12 Preparation of Intermediate 37

BuLi 2.5 M (22 ml, 55 mmol) was added dropwise to a solution of1H-pyrrolo[3,2-¾] pyridine-1-carboxylic acid, 1,1-dimethylethyl ester(10 g, 45.8 mmol) in dry THF (200 ml) at −78° C. under N₂ atmosphere.The mixture was allowed to warm to −60° C. and stirred for two hours.Then a solution of 12 (12.8 g, 50.4 mmol) in THF was slowly added at−72° C. Then the reaction mixture was stirred at room temperatureovernight. Then the reaction mixture was quenched with Na₂S₂0₃ andextracted with ethyl acetate (100 mL×3). The organic layer was washedwith H₂0 (50 mL×3), dried over Na₂S0₄, and concentrated under reducedpressure. The residue was purified by column chromatography (eluentpetroleum ether/ethyl acetate ratio 1/0 to 3/1). The product fractionswere collected and the solvent was evaporated to afford intermediate 37(2 g, 11% yield) as a yellow oil.

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 37 using the appropriatestarting materials (Table 6)

TABLE 6 Int. structure Starting materials 38

Furo[3,2-b]pyridine

Example A 13 Preparation of Intermediate 45

A reaction flask was charged with intermediate 4 (442 mg, 1.39 mmol)followed by the addition of a 9-BBN solution in THF (0.5 M, 5.5 mL, 2.8mmol, 2.0 eq.), the reaction mixture was stirred under nitrogen at roomtemperature for 2 h. THF (5 mL), K3PO4 (1.5 g, 6.9 mmol, 5 eq.) and H₂0(1.5 mL) were added and stiffing was continued for 10 min After this,intermediate 27 (401 mg, 1.9 mmol, 1.1 eq.) and PdCl₂(dppf) (101 mg,0.14 mmol, 0.1 eq.) were added, the resulting reaction mixture waspurged with nitrogen for 10 min and stirred at reflux temperature untilcomplete conversion (typically ca. 2 h). The reaction mixture wasallowed to cool to room temperature, diluted with EtOAc, washed withwater and brine, dried with MgS0₄ and concentrated under reducedpressure. The crude product was purified by silica chromatography (3%methanol in dichloromethane) to give intermediate ¥5 (110 mg, 16%yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 45 using the appropriatestarting materials (Table 7)

TABLE 7 Int. structure Starting materials 46

Intermediate 4 and 5-bromo-1-methyl- 1H-Benzimidazole 47

Intermediate 4 and 7-bromo-2,3- dimethyl- imidazo[1,2-a] pyridine 48

Intermediate 4 and intermediate 24

Example A 14 Preparation of Intermediate 50

A reaction flask was charged with intermediate 4 (560 mg, 1.75 mmol)followed by the addition of a 9-BBN solution in THF (0.5 M, 7.0 mL, 3.5mmol, 2.0 eq.), the reaction mixture was stirred under nitrogen at roomtemperature for 2 h. THF (5 mL), K3PO4 (1.9 g, 8.8 mmol, 5 eq.) and H2O(3 mL) were added and stirring was continued for 10 min. After this,intermediate 21 (407 mg, 1.9 mmol, 1.1 eq.) and PdCi2(dppf) (256 mg,0.35 mmol, 0.2 eq.) were added, the resulting reaction mixture waspurged with nitrogen for 10 min and stirred at reflux temperature untilcomplete conversion (typically ca. 3 h). The reaction mixture wasallowed to cool to room temperature, diluted with EtOAc, washed withwater and brine, dried with MgSO₄ and concentrated under reducedpressure. The crude product was purified by silica chromatography (0% to3.5% gradient of methanol in dichloro methane) to give intermediate 50(300 mg, 38% yield).

Example A 15 Preparation of Intermediate 49

A mixture of intermediate 4 (1000 mg, 3.12 mmol) in 9-BBN 0.5 M in THF(31.3 mL, 15.6 mmol) was refluxed for 1 h under N2. The mixture wascooled to room temperature, then K3PO4 (1990 mg, 9.4 mmol) in H2O (10mL) was added, followed by THF (100 mL), 7-bromo-imidazo[1,2-a]pyridine(924 mg, 4.7 mmol) and Pd-1 18 (204 mg, 0.31 mmol). The resultingmixture was refluxed for 3h. The mixture was concentrated. The residuewas dissolved in EtOAc (30 mL), washed with water (10 mL) and brine (10mL). The organic phase was dried over Na₂SO₄, filtered and concentrated.The residue was purified by chromatography column on silica (eluent:EtOAc/MeOH ratio 10/1). The desired fractions were collected andconcentrated to give intermediate 49 (486 mg, 35. 5% yield) as a solid.

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 4.9 using the appropriatestarting materials (Table 8)

TABLE 8 Int. structure Starting materials 51

Intermediate 4 and 2-amino-5- bromobenzothiazole 52

Intermediate 4 and 5-bromo-N-methyl-2- Benzothiazolamine 53

Intermediate 4 and Intermediate 32

Example A 16 Preparation of Intermediate 54

A metal pressure vessel (75 mL) charged with intermediate 50 (270 mg,0.60 mmol), THF (30 mL) and aqueous ammonia 25% (30 ml) was heated at100° C. for one day. The reaction mixture was concentrated under reducedpressure to give crude intermediate 54 which was used as such in thesubsequent step.

Example A 17 Preparation of Intermediate 55

A metal pressure vessel (75 mL) charged with intermediate Y5 (110 mg,0.23 mmol), THF (30 mL) and aqueous ammonia 25% (30 ml) was heated at100° C. for two days. The reaction mixture was concentrated underreduced pressure to give crude intermediate 55 which was used as such inthe subsequent step

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 54 and intermediate 55using the appropriate starting materials (Table 9)

TABLE 9 Starting Int. structure materials 56

Intermediate 49 NH₄OH 57

Intermediate 46 NH₄OH 58

Intermediate 51 NH₄OH 60

Intermediate 52 NH₄OH 61

Intermediate 53 NH₄OH 62

Intermediate 50 Methylamine 63

Intermediate 47 NH₄OH 64

Intermediate 48 NH₄OH 141

Intermediate 140 NHtOH

Example A18 Preparation of Intermediate 65

A mixture of intermediate 50 (500 mg, 1.1 mmol) and NaOMe (478 mg, 8.85mmol) in MeOH (15 mL) was stirred at 60° C. overnight. The mixture wasdiluted with water (20 mL) and extracted with CH2CI2 (50 mL×3). Theorganic phase was washed with brine (10 mL), dried over Na2SO₄, filteredand concentrated to give crude intermediate 65 (510 mg, 64% yield) whichused for the next step without further purification.

Example A21 Preparation of Intermediate 75

A reaction flask was charged with intermediate 9 (538 mg, 1.79 mmol)followed by the addition of a 9-BBN solution in THF (0.5 M, 12.5 mL, 6.2mmol, 3.5 eq.), the reaction mixture was stirred under nitrogen at roomtemperature for 2 h. K3PO4 (2.0 g, 8.96 mmol, 5 eq.) and H₂0 (2.5 mL)were added and stiffing was continued for 10 min. Next intermediate 29(484 mg, 1.97 mmol, 1.1 eq.) and PdCl₂(dppf) (131 mg, 0.18 mmol, 0.1eq.) were added, the reaction mixture was purged with nitrogen for 10min and heated at reflux temperature until complete conversion. Thereaction mixture was allowed to cool to room temperature and dilutedwith EtOAc, the organic phase was washed with water and brine, driedwith MgSC{circumflex over ( )} and concentrated under reduced pressure.The crude product was purified by silica chromatography (4% methanol indichloromethane) to give intermediate 75 which was used as such in thenext step.

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 75 and using theappropriate starting materials (Table 12)

TABLE 12 Int. structure Starting materials 76

Intermediate 9 and 7-Bromo-2- methylmethyl- imidazo[1,2-a] pyridine 77

Intermediate 9 and 7-Bromo-2- trifluoromethyl- imidazo[1,2-a] pyridine87

Intermediate 9 and Intermediate 34

Example A 19 Preparation of Intermediate 66

A mixture of intermediate 4 (300 mg, 0.94 mmol) in 9-BBN 0.5 M in THF(5.63 mL, 2.81 mmol) was refluxed for 1.5h under N₂. The mixture wascooled to room temperature, then K3PO4 (597 mg, 2.81 mmol) in H₂0 (2 mL)was added, followed by THF (20 mL), intermediate 35 (290.5 mg, 1.12mmol) and Pd-118 (79.5 mg, 0.112 mmol). The resulting mixture wasrefluxed for 3h. The residue was dissolved in EtOAc (30 mL), washed with(brine (5×50 mL). The organic phase was dried over Na₂S0₄, filtered andconcentrated. The residue was purified by chromatography column onsilica (eluent: EtOAc/petroleum ether ratio 2/1). The desired fractionswere collected and concentrated to give intermediate 66 (100 mg, yield21.2%) as yellow oil.

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 66 using the appropriatestarting materials (Table 10)

TABLE 10 Starting Int. structure materials 67

Intermediate 4 Intermediate 37 68

Intermediate 4 2-iodo-thieno [3,2-£] pyridine 69

Intermediate 4 Intermediate 38 70

Intermediate 9 Intermediate 36

Example A20 Preparation of Intermediate 71

Intermediate 66 (100 mg, 0.22 mmol) was dissolved in NH4OH 28% (20 ml)and dioxane (8 ml). The reaction mixture was stirred at 100° C. for 12hours in a sealed tube. The mixture was concentrated. The residue wasdissolved in ethyl acetate, washed by brine and dried over anhydrousNa₂S0₄. The organic phase was concentrated to afford intermediate 71(100 mg, 99% yield) as an oil.

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 71 using the appropriatestarting materials (Table 11).

TABLE 11 Int. structure Starting materials 72

intermediate 67 NH₄OH 73

intermediate 68 NH₄OH 74

intermediate 69 NH₄OH

Example A22 Preparation of Intermediate 78

To a solution of intermediate 1 (500 mg, 1.54 mmol, 1.0 eq) andImidazo[1,2-a]pyridin-7-ol (248.6 mg, 1.85 mmol, 1.2 eq) in THF (20 mL)was added tributylphosphane (624.9 mg, 3.1 mmol, 2.0 eq) and(NE)-N-(piperidine-1-carbonylimino)piperidine-1-carboxamide (779 mg, 3.1mmol, 2.0 eq). The mixture was stirred at 15° C. for 15 hrs. The solventwas removed. The residue was purified by flash column on silica gel(ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent from 0% to 3%MeOH/DCM gradient @ 30 mL/min) and intermediate 78 (240 mg, 33.7% yield)was obtained as a light yellow solid.

Example A23 Preparation of Intermediate 79

A solution of intermediate 78 (600 mg, 1.36 mmol, 1.0 eq) in THF (4 mL),IPA (4 niL) and NH3H2O (8 mL) was stirred at 85° C. in a sealed tube for48 hrs. The solvent was removed under reduced pressure. The residue waspurified by flash column on silica gel (ISCO®; 40 g SepaFlash® SilicaFlash Column, Eluent from 0% to 10% MeOH (NH3)/DCM gradient @ 40 mL/min)and intermediate 79 (41.5 mg, 69% yield) was obtained as a light yellowsolid.

Example A24 Preparation of Intermediate 80

To a solution of intermediate I (250 mg, 772 umol, 1.0 eq) and1H-Benzimidazol-5-ol, 1-methyl-(149 mg, 1.0 mmol, 1.3 eq) in THF (10 mL)was added PPh₃ (263 mg, 1.0 mmol, 1.30 eq.) and DIAD (203 mg, 1.0 mmol,1.3 eq). The mixture was stirred at 15° C. for 2 hrs. The solvent wasremoved. The residue was purified by flash column on silica: eluent:gradient from 0% to 50% ethyl acetate/petroleum ether and secondpurification eluent: gradient from 0% to 5% MeOH/DCM and intermediate 80(240 mg, 61.6 Vo yield) was obtained as a colorless solid.

Example A25 Preparation of Intermediate 81

To a solution of intermediate 80 (500 mg, 1.1 mmol, 1.0 eq) in THF (3niL) was added IPA (3 mL) and NH3H2O (6 mL). The mixture was stirred at85° C. for 72 hrs in a sealed tube. The solvent was removed underreduced pressure. The residue was purified by flash column on silica gel(ISCO®; 12 g SepaFlash® Silica Flash Column, eluent gradient from 0% to7% MEOH/DCM @ 30 mL/min) and intermediate 81 (370 mg, 73.5% yield) wasobtained as a white solid.

Example A27 Preparation of Intermediate 82

CS2CO3 (1.48 g, 4.55 mmol, 3 eq.) was added to a solution ofintermediate 42 (1.0 g, 1.52 mmol) and intermediate 18 (292 mg, 1.97mmol, 1.3 eq.) in DMF (20 mL). The reaction mixture was stirred at roomtemperature for 3 days after which the intermediate 82 was precipitatedby the addition of water. The precipitate was isolated by centrifugationand washed with water (re-suspension in water followed bycentrifugation). The wet product was used as such in the next step.

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 82 using the appropriatestarting materials (Table 18).

TABLE 18 Starting Int. structure materials 89

intermediate 42 intermediate 13 144

intermediate 143 and 6-azaindole

Example A33 Preparation of Intermediate 145

A solution of intermediate 144 (150 mg, 0.29 mmol),2,4-dimethoxybenzylamine hydrochloride (387 mg, 2.3 mmol) and DIPEA (112mg, 0.87 mml) in n-BuOH (0.5 ml) was stirred at 140° C. for one day. Themixture was poured into H₂0 (5 mL) and extracted with DCM (3 mL×3). Theorganic layer was washed with brine (3 mL) and dried with anhydrousNa₂S0₄ and evaporated under reduced pressure to give the crude productas brown oil.

The crude product was purified by column chromatography over silica gel(petroleum ether/ethyl acetate ratio 1:0 to petroleum ether/ethylacetate ratio 1:9). The pure fractions were collected and the solventwas evaporated under vacuum to give intermediate 145 (135 mg, 78% yield)as a brown oil.

Example A34 Preparation of Intermediate 146

Intermediate 145 (135 mg, 0.23 mmol) and TFA (2 ml) were stirred at 80°C. for 1.5 hours. The mixture was evaporated under vacuum to give thecrude intermediate 146 (100 mg) as a brown oil which was used as such inthe next step.

Example A28 Preparation of Intermediate 83

A mixture of intermediate 9 (0.5 g, 1.66 mmol) in a solution of9-Borabicyclo[3.3.1]nonane (20.0 mL, 0.5 M in THF, 10.0 mmol) wasstirred at room temperature under nitrogen atmosphere for 2 hour to havefull conversion into the 9-BBN adduct. A with nitrogen gas flushedsolution of potassium phosphate tribasic (2.83 g, 13.3 mmol) in water (5mL) was added. The reaction mixture was stirred at room temperature for10 minutes and then a with nitrogen gas flushed solution ofI,Γ-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (219 mg,0.33 mmol) and 2-amino-5-bromopyridine (288 mg, 1.66 mmol) in THF (20mL) was added. The resulting mixture was flushed through with nitrogengas for 15 minutes. The reaction mixture was stirred at 70° C. undernitrogen atmosphere for 30 minutes. The reaction mixture was dilutedwith ethyl acetate and washed twice with diluted NH₄OH and one time withwater. The organic layer was separated, dried with MgS04, filtered andthe solvents of the filtrate evaporated. The residue was dissolved indichloromethane and purified over a S1O2 column, type Grace RevelerisSRC, 4 g, Si 40, on a Armen Spot II Ultimate purification system usingdichloromethane and methanol as eluent in a gradient starting from 100%dichloromethane and ending with 10% methanol and 90% dichloromethane.The fractions containing product were combined and the solvents wereevaporated yielding intermediate 83 (0.18 g, 23% yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 83 using the appropriatestarting materials (Table 13).

TABLE 13 Intermediate Structure Starting materials 84

Intermediate 9 and 2-amino-6- bromopyridine 85

Intermediate 9 and 2-amino-4- bromopyridine 88

Intermediate 9 and 5-bromo-1h- pyrrolo[2,3-b] pyridine 100

Intermediate 99 and 2-amino-6- bromopyridine 101

Intermediate 99 and 8-bromoisoquinolin- 3-amine 102

Intermediate 99 and 3-bromopyridine 103

Intermediate 99 and 3-bromoquinoline 104

intermediate 99 and 3-bromoquinolin-8- amine 105

intermediate 99 and 2-amino-4- bromopyridine 106

intermediate 99 and 2-iodopyridine 107

intermediate 99 and 7-bromoquinoline 108

intermediate 99 and 7-bromo- imidazo[1,2-a] pyridine 109

intermediate 99 and 4-iodopyridine 110

intermediate 99 and 8-bromoquinolin-2- amine 111

intermediate 99 and 8- bromoisoquinoline 112

intermediate 99 and 8-bromoquinoline 113

intermediate 99 and 2-amino-5- bromopyridine 119

intermediate 118 and 8-bromoisoquinolin-3-amine 120

intermediate 118 and 2-amino-6- bromopyridine 121

intermediate 118 and 2-amino-5- bromopyridine 122

intermediate 118 and 2-amino-4- bromopyridine 123

intermediate 118 and 8-bromoquinoline 124

intermediate 118 and 3-bromoquinolin-8- amine 125

intermediate 118 and 7-bromoquinoline 126

intermediate 118 and 7-bromo- imidazo[1,2-a] pyridine 127

intermediate 118 and 3-bromoquinoline 128

intermediate 118 and 4-iodopyridine 129

intermediate 118 and 2-iodopyridine 130

intermediate 118 and 8-bromoquinolin-2- amine 131

intermediate 118 and 8-bromoisoquinoline 132

Intermediate 9 and 3-bromopyridine 133

Intermediate 9 and 1H-Pyrazole-1- carboxylic acid, 4- bromo-, 1,1-dimethylethyl ester 134

Intermediate 9 and 5-iodo-2-amino pyrimidine 135

Intermediate 9and 2-Pyrimidinamine, N-(4- chlorophenyl)- 5-iodo- 136

Intermediate 9 and 2- Carbamic acid, N-(7- bromoimidazol[1,2-a]pyridin-2-yl)-, 1,1- dimethylethyl ester 137

Intermediate 9 and 7-bromo-3,4- dihydro-2h- pyrido[3,2- b][1,4]oxazine138

Intermediate 9 and 5-bromo-2,3- dihydro-1h- pyrrolo[2,3-b] pyridine

Example A29 Preparation of Intermediate 86

A mixture of intermediate 9 (500 mg, 1.66 mmol), tetraethylammoniumchloride (0.30 g, 1.83 mmol) and 2-amino-5-bromopyridine (0.33 g, 1.91mmol) in DMF (15 mL) was stirred and flushed through with nitrogen gasfor 15 minutes. Then DIPEA (1.43 mL, 8.32 mmol) and Pd(OAc)2 (56.0 mg,0.25 mmol) were added. The reaction vial was sealed and the reactionmixture was stirred and heated at 100° C. for 3 days. The reactionmixture was poured into water and the product was extracted three timeswith ethyl acetate. The combined organic layers were dried with MgSO₄,filtered and the solvents of the filtrate evaporated. The residue wasdissolved in dichloromethane and purified over a Si0₂ column, type GraceReveleris SRC, 4 g, Si 40, on a Armen Spot II Ultimate purificationsystem using dichloromethane and methanol as eluent in a gradientstarting from 100% dichloromethane and ending with 10% methanol and 90%dichloromethane. The fractions containing product were combined and thesolvents were evaporated yielding 0.26 g intermediate 86 (0.26 g, 39%yield).

Below intermediates were prepared by an analogous reaction protocol aswas used for the preparation of intermediate 86 using the appropriatestarting materials (Table 20).

TABLE 20 Intermediate Structure Starting materials 90

Intermediate 9 and 5-bromo-1-methyl- 1h-imidazole 91

Intermediate 9 and 4-iodo-1-methyl- 1h-imidazole 92

Intermediate 9 and 2-amino-4- bromopyridine 93

Intermediate 9 and 2-amino-6- bromopyridine

Example A30 Preparation of Intermediate 94

A mixture of intermediate 90 (0.1 g, 0.23 mmol) in THF (30 ml) washydrogenated with Pd/C 10% (30 mg) and thiophene solution 0.4% in dipe(1 mL) at room temperature under hydrogen atmosphere until 1 eq.hydrogen was absorbed. The catalyst was removed by filtration overdicalite. The combined solvents of the filtrate were evaporated. Theresidue was dissolved in dichloromethane and purified over a Si0₂column, type Grace Reveleris SRC, 4 g, Si 40, on a Grace Reveleris X2purification system using dichloromethane and methanol as eluents in agradient starting from 100% dichloromethane to 80% dichloromethane and20% methanol. The fractions containing product were combined and thesolvents were evaporated yielding intermediate 94 (66A mg, 44% yield)

Example A32 Step 1 Preparation of Intermediate 139

Tosylhydrazine (413 mg, 2.2 mmol) was added to a solution ofintermediate 3 (1.3 g, 2.2 mmol) in MEOH (50 ml). The reaction mixturewas stirred at 60° C. for 1 hour. The reaction mixture was concentratedto dryness. The residue was purified by flash column chromatography oversilica gel (eluent: petroleum ether/ethyl acetate from 100/0 to 70/30)to give intermediate 139 as bright yellow oil.

Step 2 Preparation of Intermediate 140

Boronic acid, B-(1-methyl-1H-benzimidazo 1-5-yl)-(389 mg, 1.77 mmol),intermediate 139 (1.3 g, 2.12 mmol) and cesium carbonate (0.86 g, 2.65mmol) were stirred in dioxane (30 ml) at 110° C. under N2 for 3 hours.The reaction mixture was filtered and concentrated under vacuum. Theresidue was purified by flash column chromatography over silica gel(eluent: petroleum ether/ethyl acetate from 100/0 to 0/100). The desiredfractions were collected and the solvent was evaporated.

The residue was re-purified by preparative high-performance liquidchromatography. Column type: Gemini 150×25 mm, 5μιη, Condition: A: water(10 mM NH4HCO3); B: MeCN at the beginning: A (51%) and B (49%); at theend: A: (36%) and B (64%), Gradient Time (min) 9.5; 100% B Hold Time(min) 2.5; Flow Rate(ml/min) 30

The pure fractions were collected and the solvent was evaporated undervacuum to give intermediate 140 (100 mg, 12% yield).

B. Preparation of Final Compounds Example B1 Preparation of Compound 1

Intermediate 54 (0.59 mmol was dissolved in EtOH (5 mL), followed by theaddition of 1 M aqueous HCl (3 mL, 3.0 mmol). The resulting reactionmixture was stirred at room temperature until complete deprotection(approximately 3 days), after which it was basified by the addition ofNa₂C0₃ (253 mg) and concentrated under reduced pressure. The residue wassubjected to purification by preparative reversed phase HPLC (Stationaryphase: XBridge CI8, 3.5 μM, 4.6 mm×100 mm; mobile phase: 0.25% aqueousNH4CO3, MeOH), to give compound 1 (110 mg, 47% yield).

Example B2 Preparation of Compound 2

Intermediate 55 was dissolved in EtOH (2 mL), followed by the additionof 1 M aqueous HCl (9.86 mL, 9.86 mmol). The resulting reaction mixturewas stirred at room temperature until complete deprotection (typicallyca. 2 days), after which it was basified by the addition of aqueousammonia and concentrated under reduced pressure. The residue wasdirectly subjected to purification by preparative reversed phase HPLC(Stationary phase: XBridge C18, 3.5 μM, 4.6 mm×100 mm; mobile phase:0.25%>aqueous NH4CO3, MeOH), to give compound 2 (82 mg, 52% yield).

Below final compounds were prepared by an analogous reaction protocol aswas used for the preparation of compound 1 and compound 2 using theappropriate starting materials (Table 14)

TABLE 14 compound structure Starting materials 3

Intermediate 56  4

Intermediate 57  5

Intermediate 51  6

Intermediate 58  7

Intermediate 60  8

Intermediate 61  9

Intermediate 62  10

Intermediate 65  11

Intermediate 63  12

Intermediate 64  22

Intermediate 76  23

Intermediate 77  74

Intermediate 141

Example B 3 Preparation of Compound 16

A solution of intermediate 71 (100 mg, 0.23 mmol) in HCl 4M in MeOH (10ml) was stirred at room temperature for 1 hour. Then NH₄OH was addedinto the mixture until the pH >7. The mixture was concentrated. Theresidue was purified by prep. HPLC: Column type: Waters Xbridge Prep OBDC18: 150 x30 mm, 5μιη. Condition: A: water (0.05% ammonia hydroxidev/v); B: MeCN at the beginning: A (87%) and B (13%); at the end: A:(57%) and B (43%). Gradient Time (min) 10; 100% B Hold Time(min) 3; FlowRate(ml/min) 25 to give the 34 mg compound 16 (34 mg, 37%>yield) as awhite solid.

Below final compounds were prepared by an analogous reaction protocol aswas used for the preparation of compound 16 (using the appropriatestarting materials (Table 15)

TABLE 15 compound structure Starting materials 17

intermediate 72 18

intermediate 73 19

intermediate 74 20

intermediate 70

Example B4 Preparation of Compound 21

Intermediate 75 (1.79 mmol) was dissolved in EtOH (2 mL), followed bythe addition of 1 M aqueous HCl (9.86 mL, 9.86 mmol). The resultingreaction mixture was stirred at room temperature until completedeprotection (typically ca. 2 days), after which it was basified by theaddition of aqueous ammonia and concentrated under reduced pressure. Theresidue was directly subjected to purification by preparative reversedphase HPLC (Stationary phase: XBridge CI8, 3.5 μM, 4.6 mm×100 mm; mobilephase: 0.25% aqueous NH4CO3, MeOH), to give compound 21 (82 mg, 52%yield).

Example B5 Preparation of Compound 24

A solution of intermediate 79 (365 mg, 1.0 eg) in MeOH (3 mL) andHCl/dioxane (3 mL) was stirred at 25° C. for 2 hrs. The solvent wasremoved. The residue was adjusted to pH=7 with NH3H2O, and then waswashed with H₂0 (10 mL×2) and CH3CN (10 mL×2) to give compound 24 (235mg, 67.6% yield).

Example B6 Preparation of Compound 25

To a solution of intermediate 81 (320 mg, 736.5 umol, 1.0 eq) in MeOH(2.5 mL) was added HCl/dioxane (2.5 mL). The mixture was stirred at 20°C. for 15 hrs. The solvent was removed under reduce pressure. Theresidue was adjusted to pH>7 with NH3H2O. The mixture was crystallizedfrom H₂0 (10 mL). The precipitate was washed with CH3CN to give compound25 (230 mg, 75% yield) as a white solid.

Example B7 Preparation of Compound 26

Intermediate 82 (1.52 mmol) was dissolved in EtOH (20 mL), followed bythe addition of 1 M aqueous HCl (15.2 mL, 15.2 mmol). The reactionmixture was stirred at room temperature until complete deprotection(typical ca. 3 days), after which it was basified by the addition ofaqueous ammonia and directly subjected to purification by preparativereversed phase HPLC (Stationary phase: XBridge CI8, 3.5 μM, 4.6 mm×100mm; mobile phase: 0.25% aqueous NH4CO3, MeOH), to give compound 26 (135mg, 22.5%).

Below final compounds were prepared by an analogous reaction protocol aswas used for the preparation of compound 26 using the appropriatestarting materials (Table 19)

TABLE 19 compound structure Starting materials 33

intermediate 89

Example B8 Preparation of Compound 27

HCl (3.92 mL, 1 M in H₂0, 3.92 mmol) was added dropwise to a stirredsolution of intermediate 83 (0.18 g, 0.392 mmol) in iPrOH (5 mL) at roomtemperature. After addition the reaction mixture was stirred at roomtemperature for 3 hours. NH₃ (28% in H₂0) (0.53 mL, 7.85 mmol) wasadded. The solvents were evaporated. The residue was dissolved in 30 mLmethanol and purified with Prep HPLC (Stationary phase: RP XBridge PrepC18 OBD-10μrη, 30×150 mm, Mobile phase: 0.25% NH4HCO3 solution in water,MeOH) yielding compound 27(102 mg, 73% yield).

Below compounds were prepared by an analogous reaction protocol as wasused for the preparation of compound 27 using the appropriate startingmaterials (Table 16).

TABLE 16 Starting compound Structure materials 28

Intermediate 84 29

Intermediate 85 32

Intermediate 88 40

Intermediate 100 41

Intermediate 101 42

Intermediate 102 43

Intermediate 103 44

Intermediate 104 45

Intermediate 105 46

Intermediate 106 47

Intermediate 107 48

Intermediate 108 49

Intermediate 109 50

Intermediate 110 51

Intermediate 111 52

Intermediate 112 53

Intermediate 113 54

Intermediate 119 55

Intermediate 120 56

Intermediate 121 57

Intermediate 122 58

Intermediate 123 59

Intermediate 124 60

Intermediate 125 61

Intermediate 126 62

Intermediate 121 63

Intermediate 128 64

Intermediate 129 65

Intermediate 130 66

Intermediate 131 67

Intermediate 132 68

Intermediate 133 69

Intermediate 134 70

Intermediate 135 71

Intermediate 136 72

Intermediate 137 73

Intermediate 138

Example B9 Preparation of Compound 30

HCl (6.62 mL, 1 M in H₂0, 6.6 mmol) was added dropwise to a stirredsolution of intermediate 86 (0.26 g, 0.66 mmol) in MeOH (8 mL) at roomtemperature. After addition the reaction mixture was stirred at roomtemperature for 3 hours. NH3 (28% in H₂0) (0.90 mL, 13.2 mmol) wasadded. The solvents were evaporated. The residue was dissolved in 30 mLmethanol and purified with Prep HPLC (Stationary phase: RP XBridge PrepC18 OBD-IOμιη, 30×150 mm, Mobile phase: 0.25% NH4HCO3 solution in water,MeOH) yielding compound 30 (143 mg, 57% yield).

Below compounds were prepared by an analogous reaction protocol as wasused for the preparation of compound 30 using the appropriate startingmaterials (Table 21).

TABLE 21 Starting compound Structure materials 34

Intermediate 90 35

Intermediate 91 36

Intermediate 92 37

Intermediate 93 38

Intermediate 94 39

Intermediate 94

Example BIO Preparation of Compound 3I

To a solution of intermediate 87 (400 mg, 0.69 mmol) in MeOH (10 ml) wasadded TFA (5 ml). The mixture was stirred at room temperature for 5hours. The solvent was concentrated under vacuum. The residue was takenup into water, basified with NH3.H2O to pH >7 and extracted with ethylacetate (100 mL×2). The combined organic layers were washed with brine,dried (Na2SO₄), filtered and concentrated by vacuum to give the crudeproduct as a brown oil. The crude product was purified by preparativehigh-performance liquid chromatography:

Column: Xtimate C18 150×25 mm, 5μιη

Condition: A: water (10 mM NH4HCO3) B: ACNat the beginning: A (92%) and B (8%) at the end: A (62%) and B (38%)Gradient Time (min) 14; 100% B Hold Time (min) 2.5; Flow Rate (ml/min)25. The pure fractions were collected and the organic solvent wasevaporated under vacuum. The aqueous layer was lyophilized to dryness togive compound 31 (83 mg, 27% yield) as a white solid.

Example B11 Preparation of Compound 75

Intermediate 146 (100 mg, 0.22 mmol) and K2CO3 (270 mg) were added toMeOH (4 ml) and refluxed for 2 hours. The mixture was evaporated undervacuum. The crude product was purified by preparative HPLC. Column:Xtimate C18 150×25 mm×5μιηCondition: A: water (0.05% ammonia hydroxidev/v) B: MeCN, at the beginning: A (90%) and B (10%), at the end: A (60%)and B (40%). Gradient Time(min) 10; 100% B Hold Time(min) 2.5; FlowRate(ml/min) 25.

The pure fractions were collected and the solvent was evaporated undervacuum.The aqueous layer was lyophilized to dryness to give compound 75 (22.8mg, 28.6% yield) as a white solid.

C. Conversions of Final Compounds Example CI Preparation of Compound 13

Compound 3 (50 mg, 0.13 mmol) was stirred in DMF (2 mL).N-Chlorosuccinimide (17.6 mg, 0.13 mmol) was added. The reaction mixturewas stirred overnight. The reaction mixture was diluted to 10 mL withDMF and used as such for RP purification (XBRidge CI8_3.5 μM (100×4.6mm), aq. NH4CO3 and MeOH) yielding compound 13 (27 mg, 49.5% yield).

Below final compounds were prepared by an analogous reaction protocol aswas used for the preparation of compound 13 using the appropriatestarting materials (Table 17).

TABLE 17 compound structure Starting materials 14

Compound 3 and N- Bromosuccinimide 15

Compound 1 and N- Bromosuccinimide

Analytical Part NMR

For a number of compounds, ¹H NMR spectra were recorded on a BrukerAvance 400 operating at 400 MHz, or on a Varian 400MR spectrometeroperating at 400 MHz. As solvents Methanol-J₁ or DMSO-J₆ (deuteratedDMSO, dimethyl-d6 sulfoxide) were used. Chemical shifts (δ) are reportedin parts per million (ppm) relative to tetramethylsilane (TMS), whichwas used as internal standard.

¹H NMR (δ ppm) Compound 24 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.62 - 1.77(m, 1 H), 2.34 (s, 1 H), 2.43 (s, 1 H), 3.95 (br s, 1 H), 4.14 - 4.36(m, 3 H), 4.77 - 5.01 (m, 3 H), 6.61 (d, J = 3.5 Hz, 1 H), 6.92 (dd, J =7.5, 2.2 Hz, 1 H), 7.13 (br s, 3 H), 7.33 (d, J = 3.5 Hz, 1 H), 7.67 (s,1 H), 7.93 (s, 1 H), 8.08 (s, 1 H), 8.56 (d, J = 7.5 Hz, 1 H) Compound 3¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.39 - 1.56 (m, 1 H), 1.67 (m, J = 13.2Hz, 1 H), 1.78 - 2.00 (m, 2 H), 2.14 - 2.28 (m, 1 H), 2.58 - 2.74 (m, 2H), 3.66 - 3.78 (m, 1 H), 4.12 - 4.24 (m, 1 H), 4.62 (d, J = 4.9 Hz, 1H), 4.70 - 4.83 (m, 2 H), 6.52 (d, J = 3.5 Hz, 1 H), 6.78 (dd, J = 7.1,1.8 Hz, 1 H), 6.88 (br s, 2 H), 7.23 (d, J = 3.5 Hz, 1 H), 7.34 (s, 1H), 7.46 (s, 1 H), 7.82 (s, 1 H), 8.00 (s, 1 H), 8.43 (d, J = 7.1 Hz, 1H) Compound 33 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59 - 1.75 (m, 1 H),2.26 (s, 3 H), 2.28 - 2.45 (m, 2 H), 3.94 (br q, J = 4.0 Hz, 1 H), 4.08(dd, J = 9.2, 6.2 Hz, 1 H), 4.15 (dd, J = 9.5, 6.2 Hz, 1 H), 4.23 - 4.35(m, 1 H), 4.82 (br d, J = 4.2 Hz, 1 H), 4.86 - 4.98 (m, 2 H), 6.55 (s, 2H), 6.84 (br d, J = 1.8 Hz, 1 H), 6.90 (br s, 2 H), 7.29 (d, J = 3.5 Hz,1 H), 7.45 (s, 1 H), 8.04 (s, 1 H), 8.28 (d, J = 7.5 Hz, 1 H) Compound23 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 - 1.58 (m, 1 H), 1.71 (br s, 1H), 1.78 - 2.01 (m, 2 H), 2.24 (m, J = 12.3, 7.9, 7.9 Hz, 1 H), 2.68 -2.80 (m, 2 H), 3.67 - 3.83 (m, 1 H), 4.15 - 4.26 (m, 1 H), 4.66 (d, J =4.9 Hz, 1 H), 4.72 - 4.89 (m, 2 H), 6.54 (d, J = 3.5 Hz, 1 H), 6.92 (brs, 2 H), 7.00 (br dd, J = 7.1, 1.3 Hz, 1 H), 7.25 (d, J = 3.5 Hz, 1 H),7.49 (s, 1 H), 8.02 (s, 1 H), 8.44 (s, 1 H), 8.51 (d, J = 7.1 Hz, 1 H)Compound 26 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.68 (ddd, J = 12.5, 10.2,8.1 Hz, 1 H), 2.28 - 2.46 (m, 2 H), 2.42 (d, J = 0.7 Hz, 3 H), 3.95 (brs, 1 H), 4.14 (dd, J = 9.7, 6.2 Hz, 1 H), 4.21 (dd, J = 9.7, 6.2 Hz, 1H), 4.26 - 4.35 (m, 1 H), 4.82 (br s, 1 H), 4.85 - 4.99 (m, 2 H), 6.57(d, J = 3.5 Hz, 1 H), 6.78 (dd, J = 7.5, 2.4 Hz, 1 H), 6.92 (br s, 2 H),7.01 (d, J = 2.2 Hz, 1 H), 7.28 (s, 1 H), 7.30 (d, J = 3.5 Hz, 1 H),8.04 (s, 1 H), 8.21 (d, J =7.5 Hz, 1H) Compound 1 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.43 - 1.58 (m, 1 H), 1.62 - 1.76 (m, 1 H), 1.79 - 1.91(m, 1 H), 1.91 - 2.01 (m, 1 H), 2.24 (dt, J = 12.6, 7.9 Hz, 1 H), 2.43(d, J = 0.7 Hz, 3 H), 2.57 - 2.79 (m, 2 H), 3.75 (q, J = 5.1 Hz, 1 H),4.13 - 4.25 (m, 1 H), 4.62 (d, J = 5.1 Hz, 1 H), 4.71 - 4.90 (m, 2 H),6.54 (d, J = 3.5 Hz, 1 H), 6.84 (dd, J = 6.9, 1.7 Hz, 1 H), 6.89 (s, 2H), 7.25 (d, J = 3.5 Hz, 1 H), 7.27 (d, J = 0.7 Hz, 1 H), 7.33 (s, 1 H),8.03 (s, 1 H), 8.16 (d, J = 7.0 Hz, 1 H) Compound 11 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.43 - 1.56 (m, 1 H), 1.61 - 1.74 (m, 1 H), 1.78- 1.99(m, 2 H), 2.16 - 2.24 (m, 1 H), 2.27 (s, 3 H), 2.35 (s, 3 H), 2.59 -2.77 (m, 2 H), 3.75 (br t, J = 5.1 Hz, 1 H), 4.20 (br t, J = 6.7 Hz, 1H), 4.61 (br s, 1 H), 4.69 - 4.85 (m, 2 H), 6.54 (d, J = 3.5 Hz, 1 H),6.77 (dd, J = 7.0, 1.5 Hz, 1 H), 6.89 (br s, 2 H), 7.21 (br s, 1 H),7.24 (d, J = 3.5 Hz, 1 H), 8.03 (s, 1 H), 8.06 (d, J = 7.0 Hz, 1 H)Compound 8 ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 0.64 - 0.74 (m, 2 H),1.03 - 1.12 (m, 2 H), 1.60 - 1.74 (m, 1 H), 1.77 - 1.89 (m, 1 H), 1.89 -2.00 (m, 1 H), 2.01 - 2.13 (m, 2 H), 2.37 - 2.49 (m, 1 H), 2.76 - 2.91(m, 2 H), 3.92 (dd, J = 6.2, 4.9 Hz, 1 H), 4.34 (dd, J = 7.5, 6.2 Hz, 1H), 6.61 (d, J = 3.5 Hz, 1 H), 6.96 (dd, J = 7.1, 1.8 Hz, 1 H), 7.23 (s,1 H), 7.24 (d, J = 3.5 Hz, 1 H), 7.35 (s, 1 H), 8.06 (s, 1 H), 8.37 (d,J = 7.1 Hz, 1H) Compound 2 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.45 - 1.60(m, 1 H), 1.68 (br d, J = 4.8 Hz, 1 H), 1.85 - 2.00 (m, 2 H), 2.23 -2.35 (m, 1 H), 2.45 (s, 3 H), 2.79 (m, J = 7.4, 7.4 Hz, 2 H), 3.77 (m, J= 5.3 Hz, 1 H), 4.16 - 4.26 (m, 1 H), 4.66 (d, J = 4.8 Hz, 1 H), 4.75 -4.87 (m, 2 H), 6.54 (d, J = 3.5 Hz, 1 H), 6.89 (br s, 2 H), 7.25 (d, J =3.5 Hz, 1 H), 7.35 (s, 1 H), 7.53 (s, 1 H), 8.03 (s, 1 H), 8.50 (s, 1 H)Compound 21 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.45 - 1.60 (m, 1 H), 1.62 -1.76 (m, 1 H), 1.85 - 1.98 (m, 1 H), 2.26 - 2.36 (m, 1 H), 2.45 (d, J =0.7 Hz, 1 H), 2.84 (m, J = 6.5, 6.5 Hz, 2 H), 3.77 (br s, 1 H), 4.21 (brs, 1 H), 4.66 (br s, 1 H), 4.73 - 4.85 (m, 2 H), 6.54 (d, J = 3.5 Hz, 1H), 6.88 (br s, 2 H), 6.96 (d, J = 7.0 Hz, 1 H), 7.25 (d, J = 3.5 Hz, 1H), 7.35 (s, 1 H), 8.03 (s, 1 H), 8.21 (d, J = 7.0 Hz, 1 H) Compound 12¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.45 - 1.58 (m, 1 H), 1.71 (m, J = 8.1Hz, 1 H), 1.82 - 2.01 (m, 2 H), 2.22 - 2.32 (m, 1 H), 2.42 (s, 3 H),2.69 - 2.81 (m, 2 H), 3.71 - 3.82 (m, 1 H), 4.15 - 4.24 (m, 1 H), 4.65(br s, 1 H), 4.71 - 4.86 (m, 2 H), 6.54 (d, J = 3.5 Hz, 1 H), 6.89 (brs, 2 H), 7.25 (d, J = 3.7 Hz, 1 H), 7.34 (s, 1 H), 7.48 (d, J = 7.3 Hz,1 H), 8.03 (s, 1 H), 8.45 (d, J = 5.7 Hz, 1 H) Compound 14 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.44 - 1.60 (m, 1 H),1.63 - 1.79 (m, 1 H), 1.80 -2.03 (m, 2 H), 2.25 (dt, J = 12.6, 7.9 Hz, 1 H), 2.60 - 2.83 (m, 2 H),3.76 (q, J = 5.1 Hz, 1 H), 4.14 - 4.28 (m, 1 H), 4.62 (d, J = 5.1 Hz,1H), 4.72 - 4.87 (m, 2 H), 6.54 (d, J = 3.5 Hz, 1 H), 6.89 (s, 2 H), 7.02(dd, J = 7.0, 1.5 Hz, 1 H), 7.25 (d, J = 3.5 Hz, 1 H), 7.47 (s, 1 H),7.64 (s, 1 H), 8.03 (s, 1 H), 8.26 (d, J = 7.0 Hz, 1 H) Compound 13 ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.43 - 1.60 (m, 1 H), 1.63 - 1.80 (m, 1 H),1.85 (br s, 1 H), 1.93 (br dd, J = 14.5, 6.4 Hz, 1 H), 2.25 (dt, J =12.6, 7.9 Hz, 1 H), 2.62 - 2.85 (m, 2 H), 3.76 (q, J = 5.1 Hz, 1 H),4.13 - 4.29 (m, 1 H), 4.62 (d, J = 5.1 Hz, 1 H), 4.70 - 4.90 (m, 2 H),6.54 (d, J = 3.5 Hz,1 H), 6.89 (br s, 2 H), 7.03 (dd, J = 7.0, 1.3 Hz, 1H), 7.25 (d, J = 3.5 Hz, 1 H), 7.47 (s, 1 H), 7.62 (s, 1 H), 8.03 (s, 1H), 8.27 (d, J = 7.0 Hz,1 H), 8.27 (s, 1 H) Compound 15 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.45 - 1.57 (m, 1 H), 1.60 - 1.78 (m, 1 H), 1.78 - 2.02(m, 2 H), 2.17 - 2.28 (m, 1 H), 2.43 (s, 3 H), 2.58 - 2.77 (m, 2 H),3.73 (m, J = 5.1 Hz, 1 H), 4.16 - 4.27 (m, 1 H), 4.63 (d, J = 4.8 Hz, 1H), 4.79 (d, J = 6.3 Hz, 1 H), 4.81 - 4.92 (m, 1 H), 6.68 (br s, 2 H),6.85 (d, J = 7.0 Hz, 1 H), 7.28 (s, 1 H), 7.33 (s, 1 H), 7.59 (s, 1 H),8.08 (s, 1 H), 8.17 (d, J = 7.0 Hz, 1 H) Compound 22 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.43 - 1.58 (m, 1 H), 1.61 - 1.76 (m, 1 H), 1.80 - 2.01(m, 2 H), 2.23 (dt, J = 12.6, 7.9 Hz, 1 H), 2.29 (s, 3 H), 2.56 - 2.75(m, 2 H), 3.75 (q, J = 5.1 Hz, 1 H), 4.14 - 4.26 (m, 1 H), 4.61 (d, J =5.1 Hz, 1 H), 4.71 - 4.86 (m, 2 H), 6.54 (d, J = 3.5 Hz, 1 H), 6.72 (dd,J = 7.0, 1.5 Hz, 1 H), 6.88 (s, 2 H), 7.22 (s, 1 H), 7.24 (d, J = 3.5Hz, 1 H), 7.56 (s, 1 H), 8.03 (s, 1 H), 8.33 (d, J = 6.8 Hz, 1 H)Compound 31 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 - 1.58 (m, 1 H), 1.62 -1.76 (m, 1 H), 1.79 - 1.99 (m, 2 H), 2.05 (s, 3 H), 2.25 (dt, J = 12.4,7.6 Hz, 1 H), 2.57 - 2.79 (m, 2 H), 3.75 (q, J = 5.0 Hz, 1 H), 4.11 -4.28 (m, 1 H), 4.61 (d, J = 5.1 Hz, 1 H), 4.71 - 4.87 (m, 2 H), 6.54 (d,J = 3.5 Hz, 1 H), 6.76 (dd, J = 6.9, 1.7 Hz, 1 H), 6.89 (br s, 2 H),7.21 (s, 1 H), 7.25 (d, J = 3.5 Hz, 1 H), 7.97 (s, 1 H), 8.03 (s, 1 H),8.41 (d, J = 6.8 Hz, 1 H), 10.58 (s, 1 H) Compound 61 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.30 - 1.46 (m, 4 H) 1.56 - 1.70 (m, 3 H) 1.78 - 1.90(m,1 H) 2.17 (dt, J = 12.5, 7.9 Hz, 1 H) 2.63 (t, J = 7.6 Hz, 2 H) 3.60 -3.70 (m, 1 H) 4.13 - 4.21 (m, 1 H) 4.57 (br d, J = 4.2 Hz, 1 H) 4.71 -4.82 (m, 2 H) 6.53 (d, J = 3.5 Hz, 1 H) 6.77 (dd, J = 6.9, 1.7 Hz, 1 H)6.88 (br s, 2 H) 7.22 (d, J = 4.0 Hz, 1 H) 7.31 (br s, 1 H) 7.47 (d, J =1.1 Hz, 1 H) 7.83 (s, 1 H) 8.02 (s, 1 H) 8.42 (d, J = 6.8 Hz, 1 H)Compound 72 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 - 1.51 (m, 1 H) 1.52 -1.62 (m, 1 H) 1.68 - 1.90 (m, 2 H) 2.20 (dt, J = 12.7, 7.7 Hz, 1 H)2.33 - 2.48 (m, 2 H) 3.34 - 3.39 (m, 2 H) 3.71 (t, J = 5.0 Hz, 1 H)4.04 - 4.13 (m, 2 H) 4.19 (br t, J = 6.8 Hz, 1 H) 4.51 - 4.67 (m, 1 H)4.78 (m, J = 8.0, 8.0 Hz, 2 H) 6.39 (br s, 1 H) 6.54 (d, J = 3.5 Hz, 1H) 6.83 (d, J = 1.8 Hz, 1 H), 6.88 (br s, 2 H) 7.24 (d, J = 3.5 Hz, 1 H)7.42 (d, J = 2.0 Hz, 1 H) 8.03 (s, 1 H) Compound 56 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.23 - 1.65 (m, 7 H) 1.75 - 1.87 (m, 1 H) 2.16 (dt, J =12.5, 7.9 Hz, 1 H) 2.38 (t, J = 7.6 Hz, 2 H) 3.65 (br t, J = 5.4 Hz, 1H) 4.12 - 4.22 (m, 1 H) 4.57 (br s, 1 H) 4.70 - 4.83 (m, 2 H), 5.59 (brs, 2 H) 6.38 (d, J = 8.5 Hz, 1 H) 6.54 (d, J = 4.0 Hz, 1 H) 6.88 (br s,2 H) 7.16 - 7.27 (m, 2 H) 7.72 (d, J = 2.0 Hz, 1 H) 8.02 (s, 1 H),Compound 65 ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33 - 1.47 (m, 4 H) 1.57 -1.76 (m, 3 H) 1.82 - 1.97 (m, 1 H) 2.17 (dt, J = 12.6, 7.9 Hz, 1 H)2.93 - 3.06 (m, 2 H) 3.68 (t, J = 5.3 Hz, 1 H) 4.17 (dd, J = 7 .7, 5.9Hz, 1 H) 4.55 - 4.83 (m, 3 H) 6.29 (br s, 2 H) 6.53 (d, J = 3.5 Hz, 1 H)6.73 (d, J = 8.8 Hz, 1 H) 6.88 (br s, 2 H) 7.01 - 7.08 (m, 1 H) 7.22 (d,J = 3.5 Hz, 1 H) 7.32 (dd, J = 6.9, 1.2 Hz, 1 H) 7.43 (dd, J = 7.9, 1.3Hz, 1 H) 7.83 (d, J = 8.8 Hz, 1 H) 8.03 (s, 1 H) Compound 53 ¹H NMR (400MHz, DMSO-d₆) δ ppm 1.28 - 1.46 (m, 2 H) 1.49 - 1.61 (m, 3 H) 1.79 -1.90 (m, 1 H) 2.17 (dt, J = 12.5, 7.8 Hz, 1 H) 2.40 (br t, J = 6.9 Hz, 2H) 3.65 (br t, J = 5.1 Hz, 1 H) 4.14 (br t, J = 6.8 Hz, 1 H) 4.57 (br s,1 H) 4.68 - 4.85 (m, 2 H) 5.60 (br s, 2 H) 6.38 (d, J = 8.4 Hz, 1 H)6.52 (d, J = 3.5 Hz, 1 H) 6.87 (br s, 2 H) 7.18 - 7.25 (m, 2 H) 7.73 (d,J = 2.0 Hz, 1 H) 8.02 (s, 1 H)

LCMS (Liquid Chromatography/Mass Spectrometry)

The High Performance Liquid Chromatography (HPLC) measurement wasperformed using a LC pump, a diode-array (DAD) or a UV detector and acolumn as specified in the respective methods. If necessary, additionaldetectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which wasconfigured with an atmospheric pressure ion source. It is within theknowledge of the skilled person to set the tune parameters (e.g.scanning range, dwell time . . . ) in order to obtain ions allowing theidentification of the compound’ s nominal monoisotopic molecular weight(MW). Data acquisition was performed with appropriate software.

Compounds are described by their experimental retention times (Rt) andions. If not specified differently in the table of data, the reportedmolecular ion corresponds to the [M+H]⁺ (protonated molecule) and/or[M−H]⁻ (deprotonated molecule). In case the compound was not directlyionizable the type of adduct is specified (i.e. [M+NH₄]⁺, [M+HCOO]⁻,etc. . . . ). For molecules with multiple isotopic patterns (Br, CI),the reported value is the one obtained for the lowest isotope mass. Allresults were obtained with experimental uncertainties that are commonlyassociated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” MassSelective Detector, “RT” room temperature, “BEH” bridgedethyldioxane/silica hybrid, “DAD” Diode Array Detector, “HSS” HighStrength silica., “Q-Tof’ Quadrupole Time-of-flight mass spectrometers,“CLND”, Chemiluminescent Nitrogen Detector, “ELSD” Evaporative LightScanning Detector.

TABLE LCMS Method codes (Flow expressed in mL/min; column temperature(T) in ° C.; Run time in minutes). Method Flow Run code InstrumentColumn Mobile phase Gradient Col T time 1 Waters: Waters:HSS A: 10 mMFrom 100% A to 0.7 3.5 Acquity ® T3 CH₃COONH₄ 5% A in 2.10 min, 55UPLC ®- (1.8 μm, in 95% H₂O + to 0% A in 0.90 min DAD and 2.1 * 100 mm)5% CH₃CN to 5% A in 0.5 min SQD B: CH₃CN 2 Waters: Waters:BEH A: 10 mMFrom 95% A to 5% 0.8 2 Acquity ® C18 (1.7 μm, CH₃COONH₄ in A in 1.3 min,held 55 UPLC ®- 2.1 * 50 mm) 95% H₂O + 5% for 0.7 min. DAD and CH₃CN SQDB: CH₃CN 3 Waters: Waters:HSS A: 10 mM From 100% A to 0.7 3.5 Acquity ®T3 CH₃COONH₄ 5% A in 2.10 min, 55 UPLC ®- (1.8 μm, in 95% H₂O + to 0% Ain 0.90 min DAD and 2.1 * 100 mm) 5% CH₃CN to 5% A in 0.5 min SQD B:CH₃CN 4 Waters: Waters:HSS A: 10 mM From 100% A to 0.7 3.5 Acquity ® T3CH₃COONH₄ 5% A in 2.10 min, 55 UPLC ®- (1.8 μm, in 95% H₂O + to 0% A0.90 min DAD and 2.1 * 100 mm) 5% CH₃CN to 5% A in 0.5 min SQD B: CH₃CN5 Agilent: Phenomenex: A: CF₃COOH 0.1% 100% A for 1 min, to 0.8 101200-DAD Luna-C18 in water, B: 40% A in 4 min, to 50 and (5 μm, 2 ×CF₃COOH 0.05% in 15% A in 2.5 min, MSD6110 50 mm) CH₃CN back to 100% Ain 2 min. 6 Agilent: Waters: A: NH₄OH 100% A for 1 min, to 0.8 10.51100/1200- XBridge ™ 0.05% in water, 40% A in 4 min, held 40 DAD andShield RP18 B: CH₃CN for 2.5 min, back to MSD (5 μm, 100% A in 2 min.2.1 × 50 mm)

TABLE Co. LCMS Co. LCMS No. R_(t) [M + H]⁺ Method No. R_(t) [M + H]⁺Method 25 3.33 395 6 6 2.947 411 5 24 3.19 381 6 1 3.535 393 6 3 3.365379 6 7 1.35 425 4 4 3.558 393 6 16 2.68 393 5 5 3.732 430 5 13 1.30 4134 18 2.886 396 5 14 1.33 457 4 19 3.603 380 6 15 1.32 471 3 17 3.373 3796 8 1.31 419 4 2 1.36 427 3 61 1.24 407 4 11 1.19 407 4 72 1.13 397 4 92.777 407 5 58 1.62 418 4 10 4.057 408 6 62 1.51 418 4 12 1.24 411 3 571.15 383 4 21 1.22 427 4 47 1.41 404 4 27 0.99 355 4 55 1.21 383 4 281.04 355 1 63 1.26 368 4 29 0.45 355 2 67 1.10 340 4 30 0.98 353 4 561.18 383 4 20 1.43 471 4 54 1.42 433 4 22 3.623 393 6 49 1.17 354 4 260.49 395 2 64 1.29 368 4 23 1.38 447 4 46 1.20 354 4 31 1.09 436 4 481.16 393 4 32 1.20 379 4 59 1.51 433 4 33 1.05 395 4 50 1.42 419 4 340.93 341 4 65 1.48 433 4 35 0.97 341 4 53 1.07 369 4 36 0.96 353 4 601.49 418 4 37 1.07 353 4 52 1.50 404 4 71 0.86 395 3 51 1.40 404 4 390.90 343 4 69 1.00 356 3 38 0.90 343 4 70 1.00 466 3 41 1.34 419 4 441.41 419 4 43 1.42 404 4 68 0.98 329 4 40 1.13 369 4 66 1.49 418 4 451.08 369 4 75 1.07 365 4 42 1.18 354 4 74 1.11 379 4 73 1.12 381 4 Co.No. means compound number Retention time (R_(t)) in min n.d. means notdetermined.

Experimental Procedures In Vitro Assay (Assay 1 a and 1b)

Reagents. PRMT5-MEP50 enzyme was purchased from Charles River (Argenta).The enzyme complex was produced in insect cells (Sf9) infectedsimultaneously with two baculoviruses. One virus expresses full lengthhuman PRMT5 with Flag-tag at N-terminus, the second virus expresses fulllength MEP50 with His6-TEV cleavage at N-terminus. The protein wasaffinity purified using anti-Flag (M2) beads eluted with 3xFLAG peptide,followed by His-Select eluted with 0.5M imidazole. Eluted protein wasthen dialysed against tris-buffered saline (TBS) (pH 8.0) containing 20%glycerol and 3 mM dithiothreitol (DTT).

Full length untagged human recombinant histone H2A (residues 1-130.Genbank Accession # NM_021052, MW=14.1 kDa) expressed in E. coli waspurchased from Reaction Biology Corporation, Cat #HMT-11-146. Reagentsused for making reaction buffer or stopping reaction were purchasedincluding Tris base (Sigma Cat #T-1 503), NaCl (Sigma Cat #RGF-3270).MgCl₂ (Sigma Cat #M0250), DTT (Invitrogen Cat #15508-013) and FormicAcid (Riedel deHaen, Cat #3301.5)

High Throughput Mass Spectrometer Assay PRMT5 catalyzes the sequentialmethylations of the terminal nitrogen atoms on the guanidine groups ofarginine residues within proteins using co-substrateS-adenosyl-L-methionine (AdoMet, SAM), forming mono-methyl (MMA),symmetric-dimethyl arginine (sDMA) and S-adenosyl-L-homocysteine(AdoHey, SAH). The enzyme activity was determined by following theproduct SAH formation using high throughput mass spectrometry (AgilentRapid fire 300 System coupled to a Sciex 4000 series QTrap® triple-quadMS/MS). The reaction buffer was 20 mM Tris-HCl, pH 8.5, 50 mM NaCl, 5 mMMgCl₂ and 1 mM DTT. The reaction activity was stopped using 1% formicacid (final concentration).Inhibition Studies. The ICso Studies were performed using eleven pointdosing series made for each compound by serially diluted 1:2 in dimethylsulfoxide (DMSO), with point 12 being a DMSO control. Compounds werefirst spotted to plates, and followed by addition of 2 μM SAM and 0.6 μMH2A (histone H2A) solution mixture. The same volume of enzyme solutionwas added to initiate the enzymatic reactions. The final concentrationsof the reaction are at 1 μM SAM, 0.3 μM F₁₂A and 10 nM enzyme (assay 1a)or or 1.25 nM enzyme (assay 1b). The reaction was incubated at 30° C.for 60 minutes (min) when 10 nM enzyme was used and for 120 min when1.25 nM enzyme was used. Subsequently, the reaction was quenched byaddition of formic acid to a final concentration of 1%. The inhibitionsof SAH formation in the presence of compounds were calculated as apercentage of the control relative to the uninhibited reaction as afunction of inhibitor concentration. The data were fit as follows:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((log ICso−X)*h»

where IC50 is the inhibitor concentration (same unit as X) at 50%inhibition and h is the Hill slope. Y is percent of inhibit ion, X islog of compound concentration. Bottom and Top are the plateaus in sameunits as Y.

Experimental Procedure PD Assay (Assay 2) Reagents

A549 cells (ATCC, Cat #CCL-185) were cultured in Dulbecco's ModifiedEagle s Medium (DM EM) (Sigma, Cat #D5796), supplemented with 10% FetalCalf Serum (FCS) (HyClone™, Cat #SV30 160.03), 100 mM Sodium Pyruvate(Sigma, Cat #S8636), 200 mM L-Glutaminc (Sigma, Cat #G7513) and 50 mg/mLGentamycing (Gibco, Cat #15750-037).

Reagents used for buffers were purchased: Dulbecco s phosphate bufferedsaline (DPBS) without Ca/Mg (Sigma, Cat #D8537), phosphate bufferedsaline (PBS) 10X (Roche. Cat #1 1 666 789 001), Formalin solution 10%(Sigma, HT50-1-128-4L), Methanol 100% (Sigma, Cat #322 13-2.5 L), TritonX-100 (Acros, Cat #215680010), Bovine Serum Albumin (BSA) (Sigma, Cat#A2 153), Alexa fluor 488 goat anti-rabbit antibody (Life Technologies,Cat #A 11034), HCS Cell Mask Deep Red Stain (Life Technologies, Cat#H3272 4 Hoechst Stain (Life Technologies, Cat #33258),Anti-dimethyl-Arginine, sym (SYM TO) antibody (Millipore, 07-41 2).

Immunohistochemistry Procedure

Cells were plated at 400 cells/404L/well in 384 well black μplates clearbottom (Perkin Elmer) and overnight incubated at 37° C., 5%>CO₂. The1050 Studies were performed using nine point dosing series ranging from10 μM to 1 pM for each compound. 80 nL of the respective dilution of thecompounds was added using the Labcyte POD 810 (Labcyte) reaching a finalDMSO concentration of 0.2% in cell culture. After an incubation periodof 48h at 37° C. and 5% CO2, cells were fixed in 10% formalin solutionfor 15 min at room temperature and 20 min in ice-cold methanol, afterwhich they were washed 3x in DPBS. Subsequently, the cells were blockedfor 1 h in blocking buffer (PBS+1% BSA and 0.5% Triton X-100) andincubated overnight at 4° C. with the SYM 10 antibody diluted 1/2000 inblocking buffer. The cells were washed 3× with washing buffer (PBS+0.1%Triton X-100) and incubated with the Alexa fluor 488 goat anti-rabbitantibody diluted 1/200 in blocking buffer for 1 h at room temperature.Subsequently, they were washed 3× with washing buffer and incubated for30 min at room temperature with PBS containing a 1/5000 dilution ofHoechst Stain and a 1/5000 dilution of the HCS Cell Mask Deep Red Stain.After a final wash with PBS, the plates were imaged using the 10×W lensof the Opera® system (Perkin Elmer Life Sciences) using followingsettings (values in nm):

laser Filter camera Primary dichrome Detect dichrome 488 540/75405/488/561/635 5:10 405 450/50 405/488/561/635 5:10 635 690/50405/488/561/635 5:10

Analyses:

The inhibition of nuclear symmetric Arginine dimethylation in thepresence of compounds (% effect) was calculated as the “median nuclearSYM 10 intensity”/“median cytoplasmic SYM 10 intensity”, normalized bybelow equation:

${normalized} = {100 - {\frac{{raw} - {{lowMe}dian}}{{highMedian} - {lowMedian}}*100}}$

In the above equations, the following variable names are used:

normalized The normalized feature value raw The raw feature valuelowMedian The median of the raw values of the low control wellshighMedian The median of the raw values of the high control wells

In the above equations, the following controls were used fornormalization: Low control: minimum level of symmetrically dimethylatedArginines (cells treated with reference compound at 10 μM)

High control: maximum level of symmetrically dimethylated Arginines(DMSO treated cells).

IC50 and pIC₅₀ (−log lCso) values were calculated using the appropriatesoftware.

The pIC₅₀ values in the Table below are averaged values (Co. No. meanscompound number; n.d. means not determined).

p ICso p ICso p ICso p ICso p ICso p ICso Co. Assay Assay Assay Co.Assay Assay Assay No. 1 a 1 b 2 No. 1 a 1 b 2 25 6.9 n.d. 5.7 2 n.d. 9.88.2 24 7.5 n.d. 5.8 11 n.d. >9.7 8.4 3 8.7 n.d. 7.7 9 n.d. 8.4 7.2 4 7.9n.d. 7.5 10 n.d. 8.0 6.7 5 7.9 n.d. 5.4 12 n.d. 9.5 8.7 18 7.4 n.d. 6.921 n.d. 8.4 7.8 19 5.9 n.d. 5.3 27 n.d. 8.3 8.2 17 7.4 n.d. 6.0 28 n.d.6.8 6.2 6 8.7 n.d. 7.8 29 n.d. 6.4 5.7 1 9.1 n.d. 8.9 30 n.d. 7.2 6.3 78.2 n.d. 7.6 20 n.d. n.d. n.d. 13 8.7 8.9 7.7 22 n.d. n.d. n.d. 14 8.98.8 7.9 16 n.d. n.d. n.d. 15 n.d. 9.0 8.2 26 n.d. n.d. n.d. 8 n.d. 8.67.6 23 n.d. 7.4 n.d. p 1C₅o p 1C₅o p 1C₅o p 1C₅o p 1C₅o p 1C₅o Co. AssayAssay Assay Co. Assay Assay Assay No. 1 a 1 b 2 No. 1 a 1 b 2 31 n.d.7.2 n.d. 55 n.d. 9.4 n.d. 32 n.d. n.d. n.d. 63 n.d. 5.7 n.d. 33 n.d. 8.3n.d. 67 n.d. 6.3 n.d. 34 n.d. n.d. n.d. 56 n.d. 8.1 n.d. 35 n.d. n.d.n.d. 54 n.d. 7.0 n.d. 36 n.d. 5.7 n.d. 49 n.d. <5.6 n.d. 37 n.d. 6.1n.d. 64 n.d. 7.0 n.d. 71 n.d. 7.0 n.d. 46 n.d. <5.6 n.d. 39 n.d. 5.7n.d. 48 n.d. 7.5 n.d. 38 n.d. 6.1 n.d. 59 n.d. 5.7 n.d. 41 n.d. 6.4 n.d.68 n.d. 5.9 n.d. 44 n.d. 5.8 n.d. 50 n.d. 7.5 n.d. 43 n.d. 6.6 n.d. 65n.d. 8.0 n.d. 40 n.d. 7.1 n.d. 53 n.d. 8.7 n.d. 45 n.d. 6.3 n.d. 66 n.d.7.4 n.d. 42 n.d. 6.5 n.d. 60 n.d. 6.6 n.d. 73 n.d. 7.6 n.d. 52 n.d. <5.6n.d. 61 n.d. 8.1 n.d. 51 n.d. 6.5 n.d. 72 n.d. 7.9 n.d. 75 n.d. 6.6 n.d.58 n.d. <5.6 n.d. 69 n.d. 5.7 n.d. 62 n.d. 6.1 n.d. 70 n.d. 6.3 n.d. 57n.d. 7.1 n.d. 74 n.d. n.d. n.d. 47 n.d. 5.8 n.d.

Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates tocompounds of Formula (I), and pharmaceutically acceptable additionsalts, and solvates thereof; in particular to any one of the exemplifiedcompounds.

Typical examples of recipes for the formulation of the invention are asfollows:

Tablets Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose30 mg Talcum :10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

2. Suspension

An aqueous suspension is prepared for oral administration so that eachmilliliter contains 1 to 5 mg of active ingredient, 50 mg of sodiumcarboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol andwater ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) ofactive ingredient in 0.9% NaCl solution or in 10% by volume propyleneglycol in water.

4. Ointment

Active ingredient 5 to :1000 mg Steaiyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad :100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

1. A compound of Formula (I)

wherein R¹ represents hydrogen or —C(═O)—C₁₋₄alkyl; R² representshydrogen or —C(═O)—C₁₋₄alkyl; Y represents —CH₂— or —CF₂—; Z represents—CH₂—, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, —CR^(5a)R⁵ ^(b) —X—, —C≡C—,—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, orCR^(5a)R^(5b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R^(5h)—, R^(5a),R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), and R⁵ ^(i) eachindependently represent hydrogen or Ci-4alkyl; X represents -0, —S—, or—NR¹¹—; R¹¹ represents hydrogen, Ci-4alkyl, or Ci-4alkyl substitutedwith one substituent selected from the group consisting of —OH,-0-Ci-4alkyl, —NH₂, —NH-Ci-4alkyl, and N(Ci-₄alkyl)₂; Ar represents amonocyclic aromatic ring or a bicyclic ring system; wherein themonocyclic aromatic ring is selected from the group consisting ofpyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl; wherein the bicyclicring system is (i) a 9-membered bicyclic aromatic ring system consistingof a 6-membered ring fused with a 5-membered ring, containing one, twoor three heteroatoms each independently selected from O, S, and N, said9-membered bicyclic aromatic ring being attached to the remainder of themolecule via a ring carbon atom of the 5- or 6-membered ring, or a ringnitrogen atom of the 5-membered ring; or (ii) a 10-membered bicyclicaromatic ring system consisting of two fused 6-membered rings, whereinoptionally 1 or 2 ring carbon atoms are replaced by a nitrogen atom;provided that when the nitrogen atom replaces one of the two fusedcarbon atoms, a carbonyl group is present in said bicyclic aromatic ringsystem; provided that in case Ar represents a 10-membered bicyclicaromatic ring system, Z can only represent—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) — or _CR^(5a)R⁵ ^(b)—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —; or (iii) a fused bicyclicpartially aromatic ring system which is attached with the aromatic ringto linker Z, wherein the fused bicyclic partially aromatic ring systemis selected from (b-1), (b-2) and (b-3)

wherein ring A is a monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl and imidazolyl; whereinring B is a C₅-ecycloalkyl or a 5- to 6-membered saturated heterocyclylcontaining one or two heteroatoms each independently selected from O, Sand N; Ar is optionally substituted on the carbon atoms with in totalone, two, three or four substituents each independently selected fromthe group consisting of halo, oxo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰,cyano, —CF₃, Ci_₄alkyloxy, C₃-₆cycloalkyl, -0-C₃_6cycloalkyl,C₂-₆alkenyl, Ci_₄alkyl, and Ci_₄alkyl substituted with one Ci_₄alkyloxy;and where possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci_₄alkyl;C₃-₆cycloalkyl; Ci_₄alkyl substituted with one, two or three halo atoms;and C₃-₆cycloalkyl substituted with one, two or three halo atoms; R¹⁰represents —(C=0)-Ci_₄alkyl; C₃-₆cycloalkyl; R¹³; R¹⁴; C₃-₆cycloalkylsubstituted with one, two or three substituents each independentlyselected from the group consisting of halo, —OH and -0-Ci_₄alkyl;Ci_₄alkyl substituted with one, two or three substituents eachindependently selected from the group consisting of halo, —OH and-0-Ci_₄alkyl; or Ci_₄alkyl substituted with one substituent selectedfrom the group consisting of C₃_6cycloalkyl, R¹³ and R¹⁴; R¹³ representsa 4- to 7-membered monocyclic aromatic ring containing one, two or threeheteroatoms each independently selected from O, S, S(=0)_(p) and N; said4- to 7-membered monocyclic aromatic ring is optionally substituted withone or two substituents selected from the group consisting of Ci_₄alkyl;p represents 1 or 2; R¹⁴ represents phenyl optionally substituted withone, two or three substituents each independently selected from thegroup consisting of halo; Het represents a bicyclic aromaticheterocyclic ring system selected from the group consisting of (a-1),(a-2) and (a-3):

R³ ^(a) , R³ ^(d) and R^(3e) each independently represent hydrogen,halo, —NR⁷ ^(a) R^(7b), Ci_4 alkyl, C₂_4 alkenyl, C3-₆cycloalkyl, —OH,or -0-Ci-4alkyl; R^(7a) represents hydrogen; R^(7b) represents hydrogen,C₃-6cycloalkyl, or Ci-4alkyl; R^(4a), R^(4d), R^(4e), R^(4f) and R^(4g)each independently represent hydrogen, halo, —NR⁸ ^(a) R^(8b), orCi_₄alkyl; R⁸ ^(a) and R^(8b) each independently represent hydrogen orCi-4alkyl; Q¹ represents N or CR⁶ ^(a) ; Q² represents N or CR^(6b); Q⁸represents N or CR^(6g); Q⁹ represents N or CR^(6h); Q¹⁰ represents N orCR^(6i); Q¹¹ represents N or CR^(6j); Q⁵ represents CR³ ^(d) ; Q⁶represents N; and Q⁷ represents CR^(4f); or Q⁵ represents CR³ ^(d) ; Q⁶represents CR^(4e); and Q⁷ represents N; or Q⁵ represents N; Q⁶represents CR^(4e); and Q⁷ represents CR^(4f); or Q⁵ represents N; Q⁶represents CR^(4e); and Q⁷ represents N; or Q⁵ represents N; Q⁶represents N; and Q⁷ represents CR^(4f); or Q⁵ represents N; Q⁶represents N; and Q⁷ represents N; R⁶ ^(a) , R^(6b), R^(6g), R^(6h),R^(6i) and R⁶ each independently represent hydrogen, halogen, Ci_4alkyl, —NR⁹ ^(a) R^(9b), or Ci-4alkyl substituted with one, two or threehalo atoms; R⁹ ^(a) and R⁹ ^(b) each independently represent hydrogen orCi-₄alkyl; or a pharmaceutically acceptable addition salt or a solvatethereof.
 2. The compound according to claim 1, wherein Z represents—CH₂—, —X—CR^(5a)R^(5b)—, —CR^(5c)═CR⁵ ^(d) —, —CR^(5e)R^(5g)—CR⁵ ^(f)R⁵ ^(h) —, —CR^(5a)R^(5b)—X—, or R⁵ ^(a) , R⁵ ^(b) , R^(5c), R^(5d), R⁵^(e) , R^(5f), R^(5g), and R⁵ ^(h) each independently represent hydrogenor Ci-4alkyl; Ar represents a monocyclic aromatic ring selected frompyridinyl and imidazolyl; or a 9-membered bicyclic aromatic ring systemconsisting of a 6-membered ring fused with a 5-membered ring, containingone, two or three heteroatoms each independently selected from O, S, andN, said 9-membered bicyclic aromatic ring being attached to theremainder of the molecule via a ring carbon atom of the 5- or 6-memberedring, or a ring nitrogen atom of the 5-membered ring; Ar is optionallysubstituted on the carbon atoms with in total one, two, three or foursubstituents each independently selected from the group consisting ofhalo, —OH, —NH₂, —NH-Ci-ialkyl, —NHR¹⁰, cyano, —CF₃, C₁₋ ₄ alkyloxy,C₃-₆cycloalkyl, —O—Cs-ecycloalkyl, C₂-6alkenyl, G_₄alkyl, and C₁₋₄alkylsubstituted with one Ci-₄alkyloxy; and where possible Ar is optionallysubstituted on one N-atom with one substituent selected from the groupconsisting of Ci-₄alkyl; C₃-₆cycloalkyl; C₁₋₄alkyl substituted with one,two or three halo atoms; and C;-<, cycloalkyl substituted with one, twoor three halo atoms.
 3. The compound according to claim 1, wherein R¹represents hydrogen; R² represents hydrogen; Y represents —CH₂—; Zrepresents —CH₂, —CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, —CR^(5e)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵^(h) —, or —CR^(5a)R⁵ ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h)—; R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R^(5h), andR⁵ ^(i) each independently represent hydrogen or Ci_₄alkyl; X represents-0-; Ar represents a monocyclic aromatic ring or a bicyclic ring system;wherein the monocyclic aromatic ring is selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl; whereinthe bicyclic ring system is (i) a 9-membered bicyclic aromatic ringsystem consisting of a 6-membered ring fused with a 5-membered ring,containing one, two or three heteroatoms each independently selectedfrom O, S, and N, said 9-membered bicyclic aromatic ring being attachedto the remainder of the molecule via a ring carbon atom of the 5- or6-membered ring, or a ring nitrogen atom of the 5-membered ring; or (ii)a 10-membered bicyclic aromatic ring system consisting of two fused6-membered rings, wherein 1 or 2 ring carbon atoms are replaced by anitrogen atom; provided that when the nitrogen atom replaces one of thetwo fused carbon atoms, a carbonyl group is present in said bicyclicaromatic ring system; provided that in case Ar represents a 10-memberedbicyclic aromatic ring system, Z can only represent—CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h) — or _CR^(5a)R⁵ ^(b)—CR^(5e)R^(5d)—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —; or (iii) a fused bicyclicpartially aromatic ring system which is attached with the aromatic ringto linker Z, wherein the fused bicyclic partially aromatic ring systemis selected from (b-1) and (b-3), wherein ring A is pyridinyl; whereinring B is a 5- to 6-membered saturated heterocyclyl containing one ortwo heteroatoms each independently selected from O and N; Ar isoptionally substituted on the carbon atoms with in total one, two, threeor four substituents each independently selected from the groupconsisting of halo, oxo, —NH₂, —NH-Ci-4alkyl, —CF₃, C₃-₆cycloalkyl, andCi-4alkyl; and where possible Ar is optionally substituted on one N-atomwith one Ci-4alkyl; Het represents a bicyclic aromatic heterocyclic ringsystem (a-1); R³ ^(a) represents halo, —NR⁷ ^(a) R^(7b), or-0-Ci_₄alkyl; R⁷ ^(a) represents hydrogen; R^(7b) represents hydrogen orCi-₄alkyl; R^(4a) represents hydrogen; Q¹ represents CR⁶ ^(a) ; Q²represents N or CR^(6b); R⁶ ^(a) and R^(6b) each independently representhydrogen or halogen.
 4. The compound according to claim 2, wherein R¹represents hydrogen; R² represents hydrogen; Y represents —CH₂—; Zrepresents —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—, or—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —; R^(5a), R⁵ ^(b) , R⁵ ^(c) , R^(5d), R⁵^(e) , R⁵ ^(f) , R⁵ ^(g) , and R^(5h) represent hydrogen; X represents-0-; Ar represents a monocyclic aromatic ring selected from pyridinyland imidazolyl; or a 9-membered bicyclic aromatic ring system consistingof a 6-membered ring fused with a 5-membered ring, containing one, twoor three heteroatoms each independently selected from O, S, and N, said9-membered bicyclic aromatic ring being attached to the remainder of themolecule via a ring carbon atom of the 5- or 6-membered ring; Ar isoptionally substituted on the carbon atoms with in total one, two, threeor four substituents each independently selected from the groupconsisting of halo, —NH₂, —NH-Ci-talkyl, —CF3, C₃₋₆cycloalkyl, andG-4alkyl; and where possible Ar is optionally substituted on one N-atomwith one substituent selected from the group consisting of G-4alkyl; Hetrepresents (a-1); R^(3a) r_(e)pr_(esents) h^(a)l^(o), —NR^(7a)R^(7b), or-0-Ci-₄aikyi; R⁷ ^(a) represents hydrogen; R⁷ ^(b) represents hydrogen,or CVialkyl; R^(4a) represents hydrogen; Q¹ represents CR^(6a); Q²represents CR^(6b); R⁶ ^(a) and R^(6b) represent hydrogen, or halogen.5. The compound according to claim 1 or 2, wherein Ar represents amonocyclic aromatic ring selected from pyridinyl and imidazolyl; Ar isoptionally substituted on the carbon atoms with in total one, two, threeor four substituents each independently selected from the groupconsisting of halo, —OH, —NH₂, —NH—C₁₋₄alkyl, —NHR¹″, cyano, —CF₃,Ci-₄alkyioxy, C₃-₆cycloalkyl, —O—Cs-ecycloalkyi, C₂_6 alkenyl,Ci-₄alkyi, and Ci_₄alkyl substituted with one CVialkyloxy.
 6. Thecompound according to claim 1 or 2, wherein Ar represents a 9-memberedbicyclic aromatic ring system consisting of a 6-membered ring fused witha 5-membered ring, containing one, two or three heteroatoms eachindependently selected from O, S, and N, said 9-membered bicyclicaromatic ring being attached to the remainder of the molecule via a ringcarbon atom of the 5- or 6-membered ring, or a ring nitrogen atom of the5-membered ring; Ar is optionally substituted on the carbon atoms within total one, two, three or four substituents each independentlyselected from the group consisting of halo, —OH, —NH₂, —NH-Ci_₄alkyl,—NHR¹ ⁰ , cyano. —CF₃, G_₄alkyloxy, C₃₋ ₆ cycioalkyl, —O—Cs-ecycloalkyi,C₂-6alkenyl, Ci_₄aikyi, and Ci_₄alkyl substituted with one Ci_₄alkyioxy;and where possible Ar is optionally substituted on one N-atom with onesubstituent selected from the group consisting of Ci_₄alkyl;C3-₆cycioaikyl; Ci-₄alkyl substituted with one, two or three halo atoms;and 0-<, cyeloalkyl substituted with one. two or three halo atoms. 7.The compound according to claim 6, wherein Ar represents a monocyclicaromatic ring selected from pyridinyl and imidazolyl; or a 9-memberedbicyclic aromatic ring system selected from the group consisting of

said 9-membered bicyclic aromatic ring being attached to the remainderof the molecule via a ring carbon atom of the 5- or 6-membered ring, ora ring nitrogen atom of the 5-membered ring; Ar is optionallysubstituted on the carbon atoms with in total one, two, three or foursubstituents each independently selected from the group consisting ofhalo, —OH, —NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃, G_₄alkyloxy,C₃-₆cycloalkyl, —O-G-ecycioalkyi, C₂-6aikenyl, G_₄alkyl, and Ci_₄alkylsubstituted with one G-₄alkyloxy; and where possible Ar is optionallysubstituted on one N-atom with one substituent selected from the groupconsisting of Ci_₄alkyl; C₃-6cycloaikyl; Ci_₄alkyl substituted with one,two or three halo atoms; and C₃-6cycloalkyl substituted with one, two orthree halo atoms.
 8. The compound according to claim 1, wherein Arrepresents a monocyclic aromatic ring selected from the group consistingof pyridinyl, pyrimidinyl, pyrazolyl, and imidazolyl; Ar is optionallysubstituted on the carbon atoms with in total one, two, three or foursubstituents each independently selected from the group consisting ofhalo, —OH, —NH₂, —NH—C₁₋₄alkyl, —NHR¹⁰, cyano, —CF₃, Ci-4alkyloxy,C₃-ecycloalkyl, -0-C₃-ecycloalkyl, C₂-6alkenyl, Ci-4alkyl, and Ci-4alkylsubstituted with one Ci-4alkyloxy; and where possible Ar is optionallysubstituted on one N-atom with one substituent selected from the groupconsisting of Ci-4alkyl; C₃-₆cycloalkyl; Ci-4alkyl substituted with one,two or three halo atoms; and C₃-₆cycloalkyl substituted with one, two orthree halo atoms.
 9. The compound according to claim 1, wherein Arrepresents a bicyclic ring system; Ar is optionally substituted on thecarbon atoms with in total one, two, three or four substituents eachindependently selected from the group consisting of halo, oxo, —OH,—NH₂, —NH-Ci_₄alkyl, —NHR¹⁰, cyano, —CF₃, Ci_₄alkyloxy, C₃-₆cycloalkyl,-0-C₃_6 cycloalkyl, C₂-6alkenyl, Ci-4alkyl, and Ci-4alkyl substitutedwith one Ci_4alkyloxy; and where possible Ar is optionally substitutedon one N-atom with one substituent selected from the group consisting ofCi-4alkyl; C₃-₆cycloalkyl; Ci-4alkyl substituted with one, two or threehalo atoms; and C₃-₆cycloalkyl substituted with one, two or three haloatoms.
 10. The compound according to claim 1, wherein Z represents —CH₂,—CHR⁵ ^(i) —, —X—CR^(5a)R⁵ ^(b) —, —CR^(5c)═CR^(5d)—,—CR^(5e)R^(5g)—CR^(5f)R⁵ ^(h) —, —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵^(h) —, or —CR^(5a)R⁵ ^(b) —CR^(5c)R^(5d)—CR^(5e)R^(5g)—CR^(5i)R⁵ ^(h)—; R^(5a), R⁵ ^(b) , R^(5c), R^(5d), R^(5e), R^(5f), R^(5g), R⁵ ^(h) ,and R⁵ ^(i) each independently represent hydrogen or Ci-4alkyl; Xrepresents -0-; Het represents a bicyclic aromatic heterocyclic ringsystem (a-1); R³ ^(a) represents halo, —NR⁷ ^(a) R^(7b), or-0-Ci_₄alkyl; Q¹ represents CR⁶ ^(a) ; Q² represents CR^(6b).
 11. Thecompound according to claim 3, wherein Q² represents CR^(6b).
 12. Thecompound according to any one of claims 1 to 2 and 5 to 11, wherein R¹and R² represent hydrogen.
 13. The compound according to any one ofclaims 1 to 2 and 5 to
 12. wherein Y represents —CH₂—.
 14. The compoundaccording any one of claims 1 to 2 and 5 to 13, wherein Het represents abicyclic aromatic heterocyclic ring system of Formula (a-1).
 15. Thecompound according to claim 14, wherein R_(3a)repre_(s)ent_(s)—NR^(7a)R^(7b); and R^(7a) and R^(7b) representhydrogen.
 16. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and, as active ingredient, a therapeuticallyeffective amount of a compound according to any one of claims 1 to 15.17. A compound as defined in any one of claims 1 to 15 for use as amedicament.
 18. A compound as defined in any one of claims 1 to 15 foruse in the treatment or prevention of a disease or condition selectedfrom a blood disorder, metabolic disorders, autoimmune disorders,cancer, inflammatory diseases, cardiovascular diseases,neurodegenerative diseases, pancreatitis, multiorgan failure, kidneydiseases, platelet aggregation, sperm motility, transplantationrejection, graft rejection, and lung injuries.
 19. The compoundaccording to claim 18 wherein the disease or condition is cancer.